Modulators of the 5-hydroxytryptamine receptor 7 and their method of use

ABSTRACT

Pharmaceutical compositions of the invention comprise functionalized lactone derivatives having a disease-modifying action in the treatment of diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patent application Ser. No. 16/349,811, filed on May 14, 2019, which is a 35 U.S.C. § 371 National Stage Application of International Application No. PCT/US2017/061677, filed Nov. 15, 2017, which claims the benefit of U.S. provisional application No. 62/422,344, filed Nov. 15, 2016, which are herein incorporated by reference in their entireties.

STATEMENT OF FEDERALLY FUNDED RESEARCH

The U.S. Government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms as provided for by the terms of grant number HHSN-271-2008-00025-C awarded by the National Institute of Mental Health.

FIELD OF INVENTION

Embodiments of the invention are directed to novel compounds useful as modulators of 5-hydroxytryptamine receptor 7 (5-HT₇) activity and their method of use. Embodiments are further directed to a novel chemotype useful for the treatment diseases that are associated with dysregulation of 5-hydroxytryptamine receptor 7 activity.

BACKGROUND OF THE INVENTION

Serotonin was discovered in the late 1940s and is present in both the peripheral and central nervous systems [Physiol. Res, 60 (2011) 15-25; Psychopharmacology 213 (2011) 167-169]. Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter of the indolalkylamine group that acts at synapses of nerve cells. Seven distinct families of serotonin receptors have been identified and at least 20 subpopulations have been cloned on the basis of sequence similarity, signal transduction coupling and pharmacological characteristics. The seven families of 5-HT receptor are named 5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆, and 5-HT₇ and each of these receptors in turn has subfamilies or subpopulations. The signal transduction mechanism for all seven families have been studied and it is known that activation of 5-HT₁ and 5-HT₅ receptors causes a decrease in intracellular cAMP whereas activation of 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₆, and 5-HT₇ results in an increase in intracellular IP3 and DAG. The 5-HT pathways in the brain are important targets for drug development in the area of CNS disorders. The neurotransmitter binds to its a G-protein coupled receptor and is involved in a wide variety of actions including cognition, mood, anxiety, attention, appetite, cardiovascular function, vasoconstriction, sleep (ACS Medicinal Chemistry Letters, 2011, 2, 929-932; Physiological Research, 2011, 60, 15-25), inflammatory bowel disease (IBD), and intestinal inflammation (WO 2012058769, Khan, W. I., et. al. Journal of Immunology, 2013, 190, 4795-4804), epilepsy, seizure disorders (Epilepsy Research (2007) 75, 39), drug addiction, and alcohol addiction (Hauser, S. R. et. al. Frontiers in Neuroscience, 2015, 8, 1-9) among others.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed toward novel 5-hydroxytryptamine receptor 7 (5-HT₇) activity modulators, compounds of formula (I),

Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

A is selected from a group consisting of

X is selected from the group consisting of O, S, SO, SO₂, NR; n¹ is 0, 1, 2; n² is 0, 1, 2; R is selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl,

COR², CO₂R^(2a), CONR^(2b)R^(2c), SO₂NR^(2b)R^(2c), and SO₂R^(2d); R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) are at each occurrence independently selected from the group consisting of H, OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, —S(C₁₋₆ linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰, NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b); R² is selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(2a) is selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(2b) is selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(2c) is selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(2d) is selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl, —(CH₂)_(q)CN, —(CH₂)_(q)SO₂R¹³, —(CH₂)OR¹⁴,

R³ is selected from a group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, optionally substituted aryl,

R⁴ is an optionally substituted aryl; R^(5a) and R^(5b) are each independently optionally substituted aryl; R⁶ is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R⁷ is at each occurrence independently selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(8a) is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(8b) is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(9a) is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(9b) is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R¹⁰ is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R¹¹ is at each occurrence independently selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(12a) is at each occurrence independently selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(12b) is at each occurrence independently selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R¹³ is selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R¹⁴ is selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; n is 1, 2, or 3; m is 1 or 2; and q is 1, 2, or 3;

The present invention further relates to compositions comprising: an effective amount of one or more compounds according to the present invention and an excipient.

The present invention also relates to a method for treating or preventing diseases that involve dysregulation of 5-hydroxytryptamine receptor 7 activity, including, for example, circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral, vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulation disorder, learning disorder, memory disorder, hippocampal signaling disorder, sleep disorder, attention deficit/hyperactivity disorder, anxiety, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorders, drug addiction, and alcohol addiction said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

The present invention yet further relates to a method for treating or preventing diseases that involve dysregulation of 5-hydroxytryptamine receptor 7 activity, including, for example, circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral, vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulation disorder, learning disorder, memory disorder, hippocampal signaling disorder, sleep disorder, attention deficit/hyperactivity disorder, anxiety, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar, disorder inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorders, drug addiction, and alcohol addiction wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

The present invention also relates to a method for treating or preventing diseases or conditions associated with circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral, vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulation disorder, learning disorder, memory disorder, hippocampal signaling disorder, sleep disorder, attention deficit/hyperactivity disorder, anxiety, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorders, drug addiction, alcohol addiction and diseases that involve dysregulation of 5-hydroxytryptamine receptor 7 activity. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.

The present invention yet further relates to a method for treating or preventing diseases or conditions associated with circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral, vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulation disorder, learning disorder, memory disorder, hippocampal signaling disorder, sleep disorder, attention deficit/hyperactivity disorder, anxiety, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, and bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorders, drug addiction, alcohol addiction and diseases that involve dysregulation of 5-hydroxytryptamine receptor 7 activity, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

The present invention also relates to a method for treating or preventing diseases or conditions associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.

The present invention yet further relates to a method for treating or preventing diseases or conditions associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

The present invention further relates to a process for preparing the 5-hydroxytryptamine receptor 7 activity modulators of the present invention.

These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

There is evidence that suggests a role for the 5-HT₇ receptor in a number of medical disorders. 5-HT₇ receptor activity modulators are likely to have a beneficial effect on patients suffering from these disorders. The disorders in which 5-HT₇ dysregulation plays a role and modulation of 5-HT₇ receptor activity by a therapeutic agent may be a viable approach to therapeutic relief include, but are not limited to, circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral, vascular diseases, migraine (Vanhoenacker, P. et al. Trends in Pharmacological Sciences, 2000, 21, 2, 70-77), neuropathic pain, peripheral pain, allodynia (EP1875899), thermoregulation disorder, learning disorder, memory disorder, hippocampal signaling disorder, sleep disorder (WO20100197700) attention deficit/hyperactivity disorder (ADHD) (WO20100069390), anxiety, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder (WO20040229874), inflammatory bowel disease (IBD), intestinal inflammation (WO 2012058769, Khan, W. I., et. al. Journal of Immunology, 2013, 190, 4795-4804), epilepsy, seizure disorders (Epilepsy Research (2007) 75, 39), drug addiction, and alcohol addiction (Hauser, S. R. et. al. Frontiers in Neuroscience, 2015, 8, 1-9).

There is a long felt need for new 5-HT₇ modulators that will provide therapeutic relief from patients suffering from diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. The invention addresses the need to identify novel 5-HT₇ modulators capable of treating disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. The present invention addresses the need to develop new therapeutic agents for the treatment and prevention of circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral, vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulation disorder, learning disorder, memory disorder, hippocampal signaling disorder, sleep disorder, attention deficit/hyperactivity disorder, anxiety, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation epilepsy, seizure disorders, drug addiction, and alcohol addiction.

The 5-hydroxytryptamine receptor 7 activity modulators of the present invention are capable of treating and preventing diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, for example circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral, vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulation disorder, learning disorder, memory disorder, hippocampal signaling disorder, sleep disorder, attention deficit/hyperactivity disorder, anxiety, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorders, drug addiction, and alcohol addiction. It has been discovered that the 5-hydroxytryptamine receptor 7 play a role in a number of medical disorders, and therefore, 5-HT₇ receptor activity modulators are likely to have a beneficial effect on patients suffering from these disorders. The disorders in which 5-HT₇ dysregulation plays a role and modulation of 5-HT₇ receptor activity by a therapeutic agent may be a viable approach to therapeutic relief include, but are not limited to, circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral, vascular diseases, migraine (Vanhoenacker, P. et. al. Trends in Pharmacological Sciences, 2000, 21, 2, 70-77), neuropathic pain, peripheral pain, allodynia (EP1875899), thermoregulation disorder, learning disorder, memory disorder, hippocampal signaling disorder, sleep disorder (WO20100197700) attention deficit/hyperactivity disorder (ADHD) (WO20100069390), anxiety, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder (WO20040229874), inflammatory bowel disease (IBD), intestinal inflammation (WO 2012058769) epilepsy, seizure disorders (Epilepsy Research (2007) 75, 39), drug addiction, and alcohol addiction (Hauser, S. R. et. al. Frontiers in Neuroscience, 2015, 8, 1-9).

Without wishing to be limited by theory, it is believed that 5-hydroxytryptamine receptor 7 receptor activity modulators of the present invention can ameliorate, abate, otherwise cause to be controlled, diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity. The diseases include, but are not limited to circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral, vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulation disorder, learning disorder, memory disorder, hippocampal signaling disorder, sleep disorder, attention deficit/hyperactivity disorder, anxiety, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, bipolar disorder, inflammatory bowel disease (IBD), intestinal inflammation, epilepsy, seizure disorders, drug addiction, and alcohol addiction.

Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.

In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.

The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term “about” is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise.

It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously.

As used herein, the term “halogen” shall mean chlorine, bromine, fluorine and iodine.

As used herein, unless otherwise noted, “alkyl” and/or “aliphatic” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C₁₋₆) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Alkyl groups can be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, and the like. In substituent groups with multiple alkyl groups such as (C₁₋₆ alkyl)₂amino, the alkyl groups may be the same or different.

As used herein, the terms “alkenyl” and “alkynyl” groups, whether used alone or as part of a substituent group, refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain. Alkenyl and alkynyl groups can be optionally substituted. Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of substituted alkenyl groups include 2-chloroethenyl (also 2-chlorovinyl), 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-3,5-dien-2-yl, and the like. Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl. Nonlimiting examples of substituted alkynyl groups include, 5-hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl, 5-hydroxy-5-ethylhept-3-ynyl, and the like.

As used herein, “cycloalkyl,” whether used alone or as part of another group, refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionally substituted. Nonlimiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl. The term “cycloalkyl” also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

“Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., —CF₃, —CF₂CF₃). Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

The term “alkoxy” refers to the group —O-alkyl, wherein the alkyl group is as defined above. Alkoxy groups optionally may be substituted. The term C₃-C₆ cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). C₃-C₆ cyclic alkoxy groups optionally may be substituted.

The term “haloalkoxy” refers to the group —O-haloalkyl, wherein the haloalkyl group is as defined above. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and pentafluoroethoxyl.

The term “aryl,” wherein used alone or as part of another group, is defined herein as an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Aryl rings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms. Non-limiting examples of aryl groups include: phenyl, naphthylen-1-yl, naphthylen-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl, and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.

The term “arylalkyl” or “aralkyl” refers to the group-alkyl-aryl, where the alkyl and aryl groups are as defined herein. Aralkyl groups of the present invention are optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

The terms “heterocyclic” and/or “heterocycle” and/or “heterocylyl,” whether used alone or as part of another group, are defined herein as one or more ring having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and wherein further the ring that includes the heteroatom is non-aromatic. In heterocycle groups that include 2 or more fused rings, the non-heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocycle groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heterocycle group can be oxidized. Heterocycle groups can be optionally substituted.

Non-limiting examples of heterocyclic units having a single ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahy dropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclic units having 2 or more rings include: hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cycloocta[b]pyrrolyl.

The term “heteroaryl,” whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused rings, the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted. Non-limiting examples of heteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[cl]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, 1H-benzo[d]imidazol-2(3H)-onyl, 1H-benzo[d]imidazolyl, and isoquinolinyl.

One non-limiting example of a heteroaryl group as described above is C₁-C₅ heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S). Examples of C₁-C₅ heteroaryl include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

Unless otherwise noted, when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R² and R³ taken together with the nitrogen (N) to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The ring can be saturated or partially saturated and can be optionally substituted.

For the purposed of the present invention fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring. For example, 1,2,3,4-tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclic unit. 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:

is, for the purposes of the present invention, considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroaryl unit.

Whenever a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for “alkyl” and “aryl.”

The term “substituted” is used throughout the specification. The term “substituted” is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein below. The substituents are capable of replacing one or two hydrogen atoms of a single moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. The term “substituted” is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced. For example, difluoromethyl is a substituted C₁ alkyl; trifluoromethyl is a substituted C₁ alkyl; 4-hydroxyphenyl is a substituted aromatic ring; (N,N-dimethyl-5-amino)octanyl is a substituted C₈ alkyl; 3-guanidinopropyl is a substituted C₃ alkyl; and 2-carboxypyridinyl is a substituted heteroaryl.

The variable groups defined herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups will be so indicated.

The following are non-limiting examples of substituents which can substitute for hydrogen atoms on a moiety: halogen (chlorine (C₁), bromine (Br), fluorine (F) and iodine(I)), —CN, —NO₂, oxo (═O), —OR¹⁵, —N(R¹⁵)₂, —NR¹⁵C(O)R¹⁵, —SO₂R¹⁵, —SO₂OR¹⁵, —SO₂N(R¹⁵)₂, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃-14 cycloalkyl, aryl, heterocycle, or heteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups is optionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selected independently from halogen, —CN, —NO₂, oxo, and R¹⁵; wherein R¹⁵, at each occurrence, independently is hydrogen, —OR¹⁶, —C(O)R′⁶, —C(O)OR¹⁶, —C(O)N(R¹⁶)₂, —SO₂R¹⁶, —S(O)₂OR¹⁶, —N(R¹⁶)₂, —NR¹⁶C(O)R¹⁶, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R′⁵ units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle has 3 to 7 ring atoms; wherein R¹⁶, at each occurrence, independently is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R¹⁶ units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

In some embodiments, the substituents are selected from

-   -   i) —OR¹⁷; for example, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃;     -   ii) —C(O)R¹⁷; for example, —COCH₃, —COCH₂CH₃, —COCH₂CH₂CH₃;     -   iii) —C(O)OR¹⁷; for example, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃;     -   iv) —C(O)N(R¹⁷)₂; for example, —CONH₂, —CONHCH₃, —CON(CH₃)₂;     -   v) —N(R¹⁷)₂; for example, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃);     -   vi) halogen: —F, —Cl, —Br, and —I;     -   vii) —CH_(e)X_(g); wherein X is halogen, m is from 0 to 2,         e+g=3; for example, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃;     -   viii) —SO₂R¹⁷; for example, —SO₂H; —SO₂CH₃; —SO₂C₆H₅;     -   ix) C₁-C₆ linear, branched, or cyclic alkyl;     -   x) Cyano     -   xi) Nitro;     -   xii) N(R¹⁷)C(O)R¹⁷;     -   xiii) Oxo (═O);     -   xiv) Heterocycle; and     -   xv) Heteroaryl.         wherein each R¹⁷ is independently hydrogen, optionally         substituted C₁-C₆ linear or branched alkyl (e.g., optionally         substituted C₁-C₄ linear or branched alkyl), or optionally         substituted C₃-C₆ cycloalkyl (e.g optionally substituted C₃-C₄         cycloalkyl); or two units can be taken together to form a ring         comprising 3-7 ring atoms. In certain aspects, each R¹⁷ is         independently hydrogen, C₁-C₆ linear or branched alkyl         optionally substituted with halogen or C₃-C₆ cycloalkyl or C₃-C₆         cycloalkyl.

At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term “C₁₋₆ alkyl” is specifically intended to individually disclose C₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆, alkyl.

For the purposes of the present invention the terms “compound,” “analog,” and “composition of matter” stand equally well for the 5-hydroxytryptamine receptor 7 activity modulators described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms “compound,” “analog,” and “composition of matter” are used interchangeably throughout the present specification.

Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.

Pharmaceutically acceptable salts of compounds of the present teachings, which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation.

Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, NaH₂PO₄, Na₂HPO₄, and Na₃PO₄. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.

When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(R⁹)₂, each R⁹ may be the same or different than the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The terms “treat” and “treating” and “treatment” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer.

As used herein, “therapeutically effective” and “effective dose” refer to a substance or an amount that elicits a desirable biological activity or effect.

Except when noted, the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered. In an exemplary embodiment of the present invention, to identify subject patients for treatment according to the methods of the invention, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.

The 5-Hydroxytryptamine Receptor 7 Activity Modulators

The 5-hydroxytryptamine receptor 7 activity modulators of the present invention include all enantiomeric and diastereomeric forms alts thereof having the formula

Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: A is selected from a group consisting of

X is selected from the group consisting of O, S, SO, SO₂, NR; n¹ is 0, 1, 2; n² is 0, 1, 2; R is selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl,

COR², CO₂R^(2a), CONR^(2b)R^(2c), SO₂NR^(2b)R^(2c), and SO₂R^(2d); R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) are at each occurrence independently selected from the group consisting of H, OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, —S(C₁₋₆ linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰, NR^(9a)SO₂R¹¹, and NR^(9a)SO₂NR^(12a)R^(12b); R² is selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(2a) is selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(2b) is selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(2c) is selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(2d) is selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl, —(CH₂)_(q)CN, —(CH₂)_(q)SO₂R¹³, —(CH₂)_(q)OR¹⁴,

R³ is selected from a group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, optionally substituted aryl,

R⁴ is an optionally substituted aryl; R^(5a) and R^(5b) are each independently optionally substituted aryl; R⁶ is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R⁷ is at each occurrence independently selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(8a) is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(8b) is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(9a) is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(9b) is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R¹⁰ is at each occurrence independently selected from the group consisting of H, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R¹¹ is at each occurrence independently selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(12a) is at each occurrence independently selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R^(12b) is at each occurrence independently selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R¹³ is selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; R¹⁴ is selected from the group consisting of C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, and C₃₋₇ cycloalkyl; n is 1, 2, or 3; m is 1 or 2; and q is 1, 2, or 3;

The embodiments of the present invention include compounds having formula (II):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (III):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (IV):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (V):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (VI):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (VII):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (VIII):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (IX):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (X):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (XI):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (XII):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (XIII)

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (XIV):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (XV):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

The embodiments of the present invention include compounds having formula (XVI):

Including hydrates, solvates, enantiomers, diastereomers, pharmaceutically acceptable salts, and complexes thereof.

In some embodiments A is

In some embodiments A is

In some embodiments A is

In some embodiments A is

In some embodiments A is

In some embodiments X is O.

In some embodiments X is S.

In some embodiments X is SO.

In some embodiments X is SO₂.

In some embodiments X is NR

In some embodiments n¹ is 0.

In some embodiments n¹ is 1.

In some embodiments n¹ is 2.

In some embodiments n² is 0.

In some embodiments n² is 1.

In some embodiments n² is 2.

In some embodiments R is H.

In some embodiments R is C₁₋₆ linear alkyl.

In some embodiments R is C₃₋₇ branched alkyl.

In some embodiments R is C₃₋₇ cycloalkyl.

In some embodiments R is,

In some embodiments R is COR².

In some embodiments R is CO₂R^(2a).

In some embodiments R is CONR^(2b)R^(2c).

In some embodiments R is SO₂NR^(2b)R^(2c).

In some embodiments R is SO₂R^(2d).

In some embodiments R^(1a) is H.

In some embodiments R^(1a) is OH.

In some embodiments R^(1a) is NO₂.

In some embodiments R^(1a) is halogen.

In some embodiments R^(1a) is CN.

In some embodiments R^(1a) is C₁₋₆ linear alkyl.

In some embodiments R^(1a) is C₃₋₇ branched alkyl.

In some embodiments R^(1a) is C₃₋₇ cycloalkyl.

In some embodiments R^(1a) is C₁₋₆ linear alkoxy.

In some embodiments R^(1a) is C₃₋₇ branched alkoxy.

In some embodiments R^(1a) is C₃₋₇ cycloalkoxy.

In some embodiments R^(1a) is C₁₋₆ linear haloalkyl.

In some embodiments R^(1a) is C₃₋₇ branched haloalkyl.

In some embodiments R^(1a) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(1a) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(1a) is S(C₃₋₇ branched alkyl).

In some embodiments R^(1a) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(1a) is COR⁶.

In some embodiments R^(1a) is CO₂R⁷.

In some embodiments R^(1a) is CONR^(8a)R^(8b).

In some embodiments R^(1a) is SO₂NR^(8a)R^(8b).

In some embodiments R^(1a) is NR^(9a)R^(9b).

In some embodiments R^(1a) is NR^(9a)COR¹⁰.

In some embodiments R^(1a) is NR^(9a) SO₂R¹¹.

In some embodiments R^(1a) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(1b) is H.

In some embodiments R^(1b) is OH.

In some embodiments R^(1b) is NO₂.

In some embodiments R^(1b) is halogen.

In some embodiments R^(1b) is CN.

In some embodiments R^(1b) is C₁₋₆ linear alkyl.

In some embodiments R^(1b) is C₃₋₇ branched alkyl.

In some embodiments R^(1b) is C₃₋₇ cycloalkyl.

In some embodiments R^(1b) is C₁₋₆ linear alkoxy.

In some embodiments R^(1b) is C₃₋₇ branched alkoxy.

In some embodiments R^(1b) is C₃₋₇ cycloalkoxy.

In some embodiments R^(1b) is C₁₋₆ linear haloalkyl.

In some embodiments R^(1b) is C₃₋₇ branched haloalkyl.

In some embodiments R^(1b) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(1b) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(1b) is S(C₃₋₇ branched alkyl).

In some embodiments R^(1b) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(1b) is COR⁶.

In some embodiments R^(1b) is CO₂R⁷.

In some embodiments R^(1b) is CONR^(8a)R^(8b).

In some embodiments R^(1b) is SO₂NR^(8a)R^(8b).

In some embodiments R^(1b) is NR^(9a)R^(9b).

In some embodiments R^(1b) is NR^(9a)COR¹⁰.

In some embodiments R^(1b) is NR^(9a)SO₂R¹¹.

In some embodiments R^(1b) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(1c) is H.

In some embodiments R^(1c) is OH.

In some embodiments R^(1c) is NO₂.

In some embodiments R^(1c) is halogen.

In some embodiments R^(1c) is CN.

In some embodiments R^(1c) is C₁₋₆ linear alkyl.

In some embodiments R^(1c) is C₃₋₇ branched alkyl.

In some embodiments R^(1c) is C₃₋₇ cycloalkyl.

In some embodiments R^(1c) is C₁₋₆ linear alkoxy.

In some embodiments R^(1c) is C₃₋₇ branched alkoxy.

In some embodiments R^(1c) is C₃₋₇ cycloalkoxy.

In some embodiments R^(1c) is C₁₋₆ linear haloalkyl.

In some embodiments R^(1c) is C₃₋₇ branched haloalkyl.

In some embodiments R^(1c) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(1c) is-S(C₁₋₆ linear alkyl).

In some embodiments R^(1c) is S(C₃₋₇ branched alkyl).

In some embodiments R^(1c) is-S(C₃₋₇ cycloalkyl).

In some embodiments R^(1c) is COR⁶.

In some embodiments R^(1c) is CO₂R⁷.

In some embodiments R^(1c) is CONR^(8a)R^(8b).

In some embodiments R^(1c) is SO₂NR^(8a)R^(8b).

In some embodiments R^(1c) is NR^(9a)R^(9b).

In some embodiments R^(1c) is NR^(9a)COR¹⁰.

In some embodiments R^(1c) is NR^(9a)SO₂R¹¹.

In some embodiments R^(1c) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(1d) is H.

In some embodiments R^(1d) is OH.

In some embodiments R^(1d) is NO₂.

In some embodiments R^(1d) is halogen.

In some embodiments R^(1d) is CN.

In some embodiments R^(1d) is C₁₋₆ linear alkyl.

In some embodiments R^(1d) is C₃₋₇ branched alkyl.

In some embodiments R^(1d) is C₃₋₇ cycloalkyl.

In some embodiments R^(1d) is C₁₋₆ linear alkoxy.

In some embodiments R^(1d) is C₃₋₇ branched alkoxy.

In some embodiments R^(1d) is C₃₋₇ cycloalkoxy.

In some embodiments R^(1d) is C₁₋₆ linear haloalkyl.

In some embodiments R^(1d) is C₃₋₇ branched haloalkyl.

In some embodiments R^(1d) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(1d) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(1d) is S(C₃₋₇ branched alkyl).

In some embodiments R^(1d) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(1d) is COR⁶.

In some embodiments R^(1d) is CO₂R⁷.

In some embodiments R^(1d) is CONR^(8a)R^(8b).

In some embodiments R^(1d) is SO₂NR^(8a)R^(8b).

In some embodiments R^(1d) is NR^(9a)R^(9b).

In some embodiments R^(1d) is NR^(9a)COR¹⁰.

In some embodiments R^(1d) is NR^(9a)SO₂R¹¹.

In some embodiments R^(1d) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R^(1c) is H.

In some embodiments R^(1c) is OH.

In some embodiments R^(1c) is NO₂.

In some embodiments R^(1c) is halogen.

In some embodiments R^(1c) is CN.

In some embodiments R^(1e) is C₁₋₆ linear alkyl.

In some embodiments R^(1e) is C₃₋₇ branched alkyl.

In some embodiments R^(1e) is C₃₋₇ cycloalkyl.

In some embodiments R^(1e) is C₁₋₆ linear alkoxy.

In some embodiments R^(1e) is C₃₋₇ branched alkoxy.

In some embodiments R^(1e) is C₃₋₇ cycloalkoxy.

In some embodiments R^(1e) is C₁₋₆ linear haloalkyl.

In some embodiments R^(1e) is C₃₋₇ branched haloalkyl.

In some embodiments R^(1e) is C₁₋₆ linear haloalkoxy.

In some embodiments R^(1e) is —S(C₁₋₆ linear alkyl).

In some embodiments R^(1e) is S(C₃₋₇ branched alkyl).

In some embodiments R^(1e) is —S(C₃₋₇ cycloalkyl).

In some embodiments R^(1e) is COR⁶.

In some embodiments R^(1e) is CO₂R⁷.

In some embodiments R^(1e) is CONR^(8a)R^(8b).

In some embodiments R^(1e) is SO₂NR^(8a)R^(8b).

In some embodiments R^(1e) is NR^(9a)R^(9b).

In some embodiments R^(1e) is NR^(9a)COR¹⁰.

In some embodiments R^(1e) is NR^(9a)SO₂R¹¹.

In some embodiments R^(1e) is NR^(9a)SO₂NR^(12a)R^(12b).

In some embodiments R² is H.

In some embodiments R² is C₁₋₆ linear alkyl.

In some embodiments R² is, C₃₋₇ branched alkyl.

In some embodiments R² is C₃₋₇ cycloalkyl.

In some embodiments R^(2a) is C₁₋₆ linear alkyl.

In some embodiments R^(2a) is C₃₋₇ branched alkyl.

In some embodiments R^(2a) is C₃₋₇ cycloalkyl.

In some embodiments R^(2b) is H.

In some embodiments R^(2b) is C₁₋₆ linear alkyl.

In some embodiments R^(2b) is, C₃₋₇ branched alkyl.

In some embodiments R^(2b) is C₃₋₇ cycloalkyl.

In some embodiments R^(2c) is H.

In some embodiments R^(2c) is C₁₋₆ linear alkyl.

In some embodiments R^(2c) is, C₃₋₇ branched alkyl.

In some embodiments R^(2c) is C₃₋₇ cycloalkyl.

In some embodiments R^(2d) is C₁₋₆ linear alkyl.

In some embodiments R^(2d) is C₃₋₇ branched alkyl.

In some embodiments R^(2d) is C₃₋₇ cycloalkyl.

In some embodiments R^(2d) is C₁₋₆ linear haloalkyl.

In some embodiments R^(2d) is C₃₋₇ branched haloalkyl.

In some embodiments R^(2d) is —(CH₂)_(q)CN.

In some embodiments R^(2d) is —(CH₂)_(q)SO₂R¹³.

In some embodiments R^(2d) is —(CH₂)OR¹⁴.

In some embodiments R^(2d) is

In some embodiments R^(2d) is

In some embodiments R^(2d) is

In some embodiments R^(2d) is

In some embodiments R^(2d) is

In some embodiments R^(2d) is

In some embodiments R^(2d) is

In some embodiments R^(2d) is

In some embodiments R^(2d) is

In some embodiments R^(2d) is

In some embodiments R^(2d) is

In some embodiments R^(2d) is

In some embodiments R³ is C₁₋₆ linear alkyl.

In some embodiments R³ is C₃₋₇ branched alkyl.

In some embodiments R³ is C₃₋₇ cycloalkyl.

In some embodiments R³ is optionally substituted aryl.

In some embodiments R³ is phenyl.

In some embodiments R³ is an optionally aryl substituted with 1 to 4 units independently selected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, —S(C₁₋₆ linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰, NR^(9a)SO₂R¹¹, NR^(9a)SO₂NR^(12a)R^(12b),

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R³ is

In some embodiments R⁴ is optionally substituted aryl.

In some embodiments R⁴ is an optionally substituted aryl substituted with 1 to 4 units independently selected from the group consisting of OH, NO₂, halogen, CN, C₁₋₆ linear alkyl, C₃₋₇ branched alkyl, C₃₋₇ cycloalkyl, C₁₋₆ linear alkoxy, C₃₋₇ branched alkoxy, C₃₋₇ cycloalkoxy, C₁₋₆ linear haloalkyl, C₃₋₇ branched haloalkyl, C₁₋₆ linear haloalkoxy, —S(C₁₋₆ linear alkyl), S(C₃₋₇ branched alkyl), —S(C₃₋₇ cycloalkyl), COR⁶, CO₂R⁷, CONR^(8a)R^(8b), SO₂NR^(8a)R^(8b), NR^(9a)R^(9b), NR^(9a)COR¹⁰, NR^(9a)SO₂R¹¹, NR^(9a)SO₂NR^(12a)R^(12b),

In some embodiments R⁵ is optionally substituted aryl.

In some embodiments R⁵ is optionally substituted aryl.

In some embodiments R⁶ is H.

In some embodiments R⁶ is C₁₋₆ linear alkyl.

In some embodiments R⁶ is C₃₋₇ branched alkyl.

In some embodiments R⁶ is C₃₋₇ cycloalkyl.

In some embodiments R⁷ is C₁₋₆ linear alkyl.

In some embodiments R⁷ is C₃₋₇ branched alkyl.

In some embodiments R⁷ is C₃₋₇ cycloalkyl.

In some embodiments R^(8a) is H.

In some embodiments R^(8a) is C₁₋₆ linear alkyl.

In some embodiments R^(8a) is C₃₋₇ branched alkyl.

In some embodiments R^(8a) is C₃₋₇ cycloalkyl.

In some embodiments R^(8b) is H.

In some embodiments R^(8b) is C₁₋₆ linear alkyl.

In some embodiments R^(8b) is C₃₋₇ branched alkyl.

In some embodiments R^(8b) is C₃₋₇ cycloalkyl.

In some embodiments R^(9a) is H.

In some embodiments R^(9a) is C₁₋₆ linear alkyl.

In some embodiments R^(9a) is C₃₋₇ branched alkyl.

In some embodiments R^(9a) is C₃₋₇ cycloalkyl.

In some embodiments R^(9b) is H.

In some embodiments R^(9b) is C₁₋₆ linear alkyl.

In some embodiments R^(9b) is C₃₋₇ branched alkyl.

In some embodiments R^(9b) is C₃₋₇ cycloalkyl.

In some embodiments R¹⁰ is H.

In some embodiments R¹⁰ is C₁₋₆ linear alkyl.

In some embodiments R¹⁰ is C₃₋₇ branched alkyl.

In some embodiments R¹⁰ is C₃₋₇ cycloalkyl.

In some embodiments R¹¹ is C₁₋₆ linear alkyl.

In some embodiments R¹¹ is C₃₋₇ branched alkyl.

In some embodiments R¹¹ is C₃₋₇ cycloalkyl.

In some embodiments R¹⁰ is C₁₋₆ linear alkyl.

In some embodiments R¹⁰ is C₃₋₇ branched alkyl.

In some embodiments R¹⁰ is C₃₋₇ cycloalkyl.

In some embodiments R^(12a) is C₁₋₆ linear alkyl.

In some embodiments R^(12a) is C₃₋₇ branched alkyl.

In some embodiments R^(12a) is C₃₋₇ cycloalkyl.

In some embodiments R^(12b) is C₁₋₆ linear alkyl.

In some embodiments R^(12b) is C₃₋₇ branched alkyl.

In some embodiments R^(12b) is C₃₋₇ cycloalkyl.

In some embodiments R¹³ is C₁₋₆ linear alkyl.

In some embodiments R¹³ is C₃₋₇ branched alkyl.

In some embodiments R¹³ is C₃₋₇ cycloalkyl.

In some embodiments R¹⁴ is C₁₋₆ linear alkyl.

In some embodiments R¹⁴ is C₃₋₇ branched alkyl.

In some embodiments R¹⁴ is C₃₋₇ cycloalkyl.

In some embodiments n is 1.

In some embodiments n is 2.

In some embodiments n is 3.

In some embodiments m is 1.

In some embodiments m is 2.

In some embodiments q is 1.

In some embodiments q is 2.

In some embodiments q is 3.

Exemplary embodiments include compounds having the formula (XVII)

or a pharmaceutically acceptable salt form thereof defined herein below in Table 1.

TABLE 1 Entry n R R³ 1 1 H Phenyl 2 2 H Phenyl 3 3 H Phenyl 4 1 Me Phenyl 5 2 Me Phenyl 6 3 Me Phenyl 7 1 CH₂Ph Phenyl 8 2 CH₂Ph Phenyl 9 3 CH₂Ph Phenyl 10 1 COMe Phenyl 11 2 COMe Phenyl 12 3 COMe Phenyl 13 1 CO₂Me Phenyl 14 2 CO₂Me Phenyl 15 3 CO₂Me Phenyl 16 1 CO₂tBu Phenyl 17 2 CO₂tBu Phenyl 18 3 CO₂tBu Phenyl 19 1 CONHMe Phenyl 20 2 CONHMe Phenyl 21 3 CONHMe Phenyl 22 1 SO₂Me Phenyl 23 2 SO₂Me Phenyl 24 3 SO₂Me Phenyl 25 1 SO₂NH₂ Phenyl 26 2 SO₂NH₂ Phenyl 27 3 SO₂NH₂ Phenyl 28 1 H 3-OH-Phenyl 29 2 H 3-OH-Phenyl 30 3 H 3-OH-Phenyl 31 1 Me 3-OH-Phenyl 32 2 Me 3-OH-Phenyl 33 3 Me 3-OH-Phenyl 34 1 CH₂Ph 3-OH-Phenyl 35 2 CH₂Ph 3-OH-Phenyl 36 3 CH₂Ph 3-OH-Phenyl 37 1 COMe 3-OH-Phenyl 38 2 COMe 3-OH-Phenyl 39 3 COMe 3-OH-Phenyl 40 1 CO₂Me 3-OH-Phenyl 41 2 CO₂Me 3-OH-Phenyl 42 3 CO₂Me 3-OH-Phenyl 43 1 CO₂tBu 3-OH-Phenyl 44 2 CO₂tBu 3-OH-Phenyl 45 3 CO₂tBu 3-OH-Phenyl 46 1 CONHMe 3-OH-Phenyl 47 2 CONHMe 3-OH-Phenyl 48 3 CONHMe 3-OH-Phenyl 49 1 SO₂Me 3-OH-Phenyl 50 2 SO₂Me 3-OH-Phenyl 51 3 SO₂Me 3-OH-Phenyl 52 1 SO₂NH₂ 3-OH-Phenyl 53 2 SO₂NH₂ 3-OH-Phenyl 54 3 SO₂NH₂ 3-OH-Phenyl 55 1 H 4-NO₂-Phenyl 56 2 H 4-NO₂-Phenyl 57 3 H 4-NO₂-Phenyl 58 1 Me 4-NO₂-Phenyl 59 2 Me 4-NO₂-Phenyl 60 3 Me 4-NO₂-Phenyl 61 1 CH₂Ph 4-NO₂-Phenyl 62 2 CH₂Ph 4-NO₂-Phenyl 63 3 CH₂Ph 4-NO₂-Phenyl 64 1 COMe 4-NO₂-Phenyl 65 2 COMe 4-NO₂-Phenyl 66 3 COMe 4-NO₂-Phenyl 67 1 CO₂Me 4-NO₂-Phenyl 68 2 CO₂Me 4-NO₂-Phenyl 69 3 CO₂Me 4-NO₂-Phenyl 70 1 CO₂tBu 4-NO₂-Phenyl 71 2 CO₂tBu 4-NO₂-Phenyl 72 3 CO₂tBu 4-NO₂-Phenyl 73 1 CONHMe 4-NO₂-Phenyl 74 2 CONHMe 4-NO₂-Phenyl 75 3 CONHMe 4-NO₂-Phenyl 76 1 SO₂Me 4-NO₂-Phenyl 77 2 SO₂Me 4-NO₂-Phenyl 78 3 SO₂Me 4-NO₂-Phenyl 79 1 SO₂NH₂ 4-NO₂-Phenyl 80 2 SO₂NH₂ 4-NO₂-Phenyl 81 3 SO₂NH₂ 4-NO₂-Phenyl 82 1 H 3-OMe-Phenyl 83 2 H 3-OMe-Phenyl 84 3 H 3-OMe-Phenyl 85 1 Me 3-OMe-Phenyl 86 2 Me 3-OMe-Phenyl 87 3 Me 3-OMe-Phenyl 88 1 CH₂Ph 3-OMe-Phenyl 89 2 CH₂Ph 3-OMe-Phenyl 90 3 CH₂Ph 3-OMe-Phenyl 91 1 COMe 3-OMe-Phenyl 92 2 COMe 3-OMe-Phenyl 93 3 COMe 3-OMe-Phenyl 94 1 CO₂Me 3-OMe-Phenyl 95 2 CO₂Me 3-OMe-Phenyl 96 3 CO₂Me 3-OMe-Phenyl 97 1 CO₂tBu 3-OMe-Phenyl 98 2 CO₂tBu 3-OMe-Phenyl 99 3 CO₂tBu 3-OMe-Phenyl 100 1 CONHMe 3-OMe-Phenyl 101 2 CONHMe 3-OMe-Phenyl 102 3 CONHMe 3-OMe-Phenyl 103 1 SO₂Me 3-OMe-Phenyl 104 2 SO₂Me 3-OMe-Phenyl 105 3 SO₂Me 3-OMe-Phenyl 106 1 SO₂NH₂ 3-OMe-Phenyl 107 2 SO₂NH₂ 3-OMe-Phenyl 108 3 SO₂NH₂ 3-OMe-Phenyl 109 1 H 4-CN-Phenyl 110 2 H 4-CN-Phenyl 111 3 H 4-CN-Phenyl 112 1 Me 4-CN-Phenyl 113 2 Me 4-CN-Phenyl 114 3 Me 4-CN-Phenyl 115 1 CH₂Ph 4-CN-Phenyl 116 2 CH₂Ph 4-CN-Phenyl 117 3 CH₂Ph 4-CN-Phenyl 118 1 COMe 4-CN-Phenyl 119 2 COMe 4-CN-Phenyl 120 3 COMe 4-CN-Phenyl 121 1 CO₂Me 4-CN-Phenyl 122 2 CO₂Me 4-CN-Phenyl 123 3 CO₂Me 4-CN-Phenyl 124 1 CO₂tBu 4-CN-Phenyl 125 2 CO₂tBu 4-CN-Phenyl 126 3 CO₂tBu 4-CN-Phenyl 127 1 CONHMe 4-CN-Phenyl 128 2 CONHMe 4-CN-Phenyl 129 3 CONHMe 4-CN-Phenyl 130 1 SO₂Me 4-CN-Phenyl 131 2 SO₂Me 4-CN-Phenyl 132 3 SO₂Me 4-CN-Phenyl 133 1 SO₂NH₂ 4-CN-Phenyl 134 2 SO₂NH₂ 4-CN-Phenyl 135 3 SO₂NH₂ 4-CN-Phenyl 136 1 H 2-CN-Phenyl 137 2 H 2-CN-Phenyl 138 3 H 2-CN-Phenyl 139 1 Me 2-CN-Phenyl 140 2 Me 2-CN-Phenyl 141 3 Me 2-CN-Phenyl 142 1 CH₂Ph 2-CN-Phenyl 143 2 CH₂Ph 2-CN-Phenyl 144 3 CH₂Ph 2-CN-Phenyl 145 1 COMe 2-CN-Phenyl 146 2 COMe 2-CN-Phenyl 147 3 COMe 2-CN-Phenyl 148 1 CO₂Me 2-CN-Phenyl 149 2 CO₂Me 2-CN-Phenyl 150 3 CO₂Me 2-CN-Phenyl 151 1 CO₂tBu 2-CN-Phenyl 152 2 CO₂tBu 2-CN-Phenyl 153 3 CO₂tBu 2-CN-Phenyl 154 1 CONHMe 2-CN-Phenyl 155 2 CONHMe 2-CN-Phenyl 156 3 CONHMe 2-CN-Phenyl 157 1 SO₂Me 2-CN-Phenyl 158 2 SO₂Me 2-CN-Phenyl 159 3 SO₂Me 2-CN-Phenyl 160 1 SO₂NH₂ 2-CN-Phenyl 161 2 SO₂NH₂ 2-CN-Phenyl 162 3 SO₂NH₂ 2-CN-Phenyl 163 1 H 3-Me-Phenyl 164 2 H 3-Me-Phenyl 165 3 H 3-Me-Phenyl 166 1 Me 3-Me-Phenyl 167 2 Me 3-Me-Phenyl 168 3 Me 3-Me-Phenyl 169 1 CH₂Ph 3-Me-Phenyl 170 2 CH₂Ph 3-Me-Phenyl 171 3 CH₂Ph 3-Me-Phenyl 172 1 COMe 3-Me-Phenyl 173 2 COMe 3-Me-Phenyl 174 3 COMe 3-Me-Phenyl 175 1 CO₂Me 3-Me-Phenyl 176 2 CO₂Me 3-Me-Phenyl 177 3 CO₂Me 3-Me-Phenyl 178 1 CO₂tBu 3-Me-Phenyl 179 2 CO₂tBu 3-Me-Phenyl 180 3 CO₂tBu 3-Me-Phenyl 181 1 CONHMe 3-Me-Phenyl 182 2 CONHMe 3-Me-Phenyl 183 3 CONHMe 3-Me-Phenyl 184 1 SO₂Me 3-Me-Phenyl 185 2 SO₂Me 3-Me-Phenyl 186 3 SO₂Me 3-Me-Phenyl 187 1 SO₂NH₂ 3-Me-Phenyl 188 2 SO₂NH₂ 3-Me-Phenyl 189 3 SO₂NH₂ 3-Me-Phenyl 190 1 H 2-F-Phenyl 191 2 H 2-F-Phenyl 192 3 H 2-F-Phenyl 193 1 Me 2-F-Phenyl 194 2 Me 2-F-Phenyl 195 3 Me 2-F-Phenyl 196 1 CH₂Ph 2-F-Phenyl 197 2 CH₂Ph 2-F-Phenyl 198 3 CH₂Ph 2-F-Phenyl 199 1 COMe 2-F-Phenyl 200 2 COMe 2-F-Phenyl 201 3 COMe 2-F-Phenyl 202 1 CO₂Me 2-F-Phenyl 203 2 CO₂Me 2-F-Phenyl 204 3 CO₂Me 2-F-Phenyl 205 1 CO₂tBu 2-F-Phenyl 206 2 CO₂tBu 2-F-Phenyl 207 3 CO₂tBu 2-F-Phenyl 208 1 CONHMe 2-F-Phenyl 209 2 CONHMe 2-F-Phenyl 210 3 CONHMe 2-F-Phenyl 211 1 SO₂Me 2-F-Phenyl 212 2 SO₂Me 2-F-Phenyl 213 3 SO₂Me 2-F-Phenyl 214 1 SO₂NH₂ 2-F-Phenyl 215 2 SO₂NH₂ 2-F-Phenyl 216 3 SO₂NH₂ 2-F-Phenyl 217 1 H 4-F-Phenyl 218 2 H 4-F-Phenyl 219 3 H 4-F-Phenyl 220 1 Me 4-F-Phenyl 221 2 Me 4-F-Phenyl 222 3 Me 4-F-Phenyl 223 1 CH₂Ph 4-F-Phenyl 224 2 CH₂Ph 4-F-Phenyl 225 3 CH₂Ph 4-F-Phenyl 226 1 COMe 4-F-Phenyl 227 2 COMe 4-F-Phenyl 228 3 COMe 4-F-Phenyl 229 1 CO₂Me 4-F-Phenyl 230 2 CO₂Me 4-F-Phenyl 231 3 CO₂Me 4-F-Phenyl 232 1 CO₂tBu 4-F-Phenyl 233 2 CO₂tBu 4-F-Phenyl 234 3 CO₂tBu 4-F-Phenyl 235 1 CONHMe 4-F-Phenyl 236 2 CONHMe 4-F-Phenyl 237 3 CONHMe 4-F-Phenyl 238 1 SO₂Me 4-F-Phenyl 239 2 SO₂Me 4-F-Phenyl 240 3 SO₂Me 4-F-Phenyl 241 1 SO₂NH₂ 4-F-Phenyl 242 2 SO₂NH₂ 4-F-Phenyl 243 3 SO₂NH₂ 4-F-Phenyl 244 1 H 3-Cl-Phenyl 245 2 H 3-Cl-Phenyl 246 3 H 3-Cl-Phenyl 247 1 Me 3-Cl-Phenyl 248 2 Me 3-Cl-Phenyl 249 3 Me 3-Cl-Phenyl 250 1 CH₂Ph 3-Cl-Phenyl 251 2 CH₂Ph 3-Cl-Phenyl 252 3 CH₂Ph 3-Cl-Phenyl 253 1 COMe 3-Cl-Phenyl 254 2 COMe 3-Cl-Phenyl 255 3 COMe 3-Cl-Phenyl 256 1 CO₂Me 3-Cl-Phenyl 257 2 CO₂Me 3-Cl-Phenyl 258 3 CO₂Me 3-Cl-Phenyl 259 1 CO₂tBu 3-Cl-Phenyl 260 2 CO₂tBu 3-Cl-Phenyl 261 3 CO₂tBu 3-Cl-Phenyl 262 1 CONHMe 3-Cl-Phenyl 263 2 CONHMe 3-Cl-Phenyl 264 3 CONHMe 3-Cl-Phenyl 265 1 SO₂Me 3-Cl-Phenyl 266 2 SO₂Me 3-Cl-Phenyl 267 3 SO₂Me 3-Cl-Phenyl 268 1 SO₂NH₂ 3-Cl-Phenyl 269 2 SO₂NH₂ 3-Cl-Phenyl 270 3 SO₂NH₂ 3-Cl-Phenyl 271 1 H 2-Br-Phenyl 272 2 H 2-Br-Phenyl 273 3 H 2-Br-Phenyl 274 1 Me 2-Br-Phenyl 275 2 Me 2-Br-Phenyl 276 3 Me 2-Br-Phenyl 277 1 CH₂Ph 2-Br-Phenyl 278 2 CH₂Ph 2-Br-Phenyl 279 3 CH₂Ph 2-Br-Phenyl 280 1 COMe 2-Br-Phenyl 281 2 COMe 2-Br-Phenyl 282 3 COMe 2-Br-Phenyl 283 1 CO₂Me 2-Br-Phenyl 284 2 CO₂Me 2-Br-Phenyl 285 3 CO₂Me 2-Br-Phenyl 286 1 CO₂tBu 2-Br-Phenyl 287 2 CO₂tBu 2-Br-Phenyl 288 3 CO₂tBu 2-Br-Phenyl 289 1 CONHMe 2-Br-Phenyl 290 2 CONHMe 2-Br-Phenyl 291 3 CONHMe 2-Br-Phenyl 292 1 SO₂Me 2-Br-Phenyl 293 2 SO₂Me 2-Br-Phenyl 294 3 SO₂Me 2-Br-Phenyl 295 1 SO₂NH₂ 2-Br-Phenyl 296 2 SO₂NH₂ 2-Br-Phenyl 297 3 SO₂NH₂ 2-Br-Phenyl 298 1 H 4-Br-Phenyl 299 2 H 4-Br-Phenyl 300 3 H 4-Br-Phenyl 301 1 Me 4-Br-Phenyl 302 2 Me 4-Br-Phenyl 303 3 Me 4-Br-Phenyl 304 1 CH₂Ph 4-Br-Phenyl 305 2 CH₂Ph 4-Br-Phenyl 306 3 CH₂Ph 4-Br-Phenyl 307 1 COMe 4-Br-Phenyl 308 2 COMe 4-Br-Phenyl 309 3 COMe 4-Br-Phenyl 310 1 CO₂Me 4-Br-Phenyl 311 2 CO₂Me 4-Br-Phenyl 312 3 CO₂Me 4-Br-Phenyl 313 1 CO₂tBu 4-Br-Phenyl 314 2 CO₂tBu 4-Br-Phenyl 315 3 CO₂tBu 4-Br-Phenyl 316 1 CONHMe 4-Br-Phenyl 317 2 CONHMe 4-Br-Phenyl 318 3 CONHMe 4-Br-Phenyl 319 1 SO₂Me 4-Br-Phenyl 320 2 SO₂Me 4-Br-Phenyl 321 3 SO₂Me 4-Br-Phenyl 322 1 SO₂NH₂ 4-Br-Phenyl 323 2 SO₂NH₂ 4-Br-Phenyl 324 3 SO₂NH₂ 4-Br-Phenyl 325 1 H 3-CF₃-Phenyl 326 2 H 3-CF₃-Phenyl 327 3 H 3-CF₃-Phenyl 328 1 Me 3-CF₃-Phenyl 329 2 Me 3-CF₃-Phenyl 330 3 Me 3-CF₃-Phenyl 331 1 CH₂Ph 3-CF₃-Phenyl 332 2 CH₂Ph 3-CF₃-Phenyl 333 3 CH₂Ph 3-CF₃-Phenyl 334 1 COMe 3-CF₃-Phenyl 335 2 COMe 3-CF₃-Phenyl 336 3 COMe 3-CF₃-Phenyl 337 1 CO₂Me 3-CF₃-Phenyl 338 2 CO₂Me 3-CF₃-Phenyl 339 3 CO₂Me 3-CF₃-Phenyl 340 1 CO₂tBu 3-CF₃-Phenyl 341 2 CO₂tBu 3-CF₃-Phenyl 342 3 CO₂tBu 3-CF₃-Phenyl 343 1 CONHMe 3-CF₃-Phenyl 344 2 CONHMe 3-CF₃-Phenyl 345 3 CONHMe 3-CF₃-Phenyl 346 1 SO₂Me 3-CF₃-Phenyl 347 2 SO₂Me 3-CF₃-Phenyl 348 3 SO₂Me 3-CF₃-Phenyl 349 1 SO₂NH₂ 3-CF₃-Phenyl 350 2 SO₂NH₂ 3-CF₃-Phenyl 351 3 SO₂NH₂ 3-CF₃-Phenyl 352 1 H 2-iPr-Phenyl 353 2 H 2-iPr-Phenyl 354 3 H 2-iPr-Phenyl 355 1 Me 2-iPr-Phenyl 356 2 Me 2-iPr-Phenyl 357 3 Me 2-iPr-Phenyl 358 1 CH₂Ph 2-iPr-Phenyl 359 2 CH₂Ph 2-iPr-Phenyl 360 3 CH₂Ph 2-iPr-Phenyl 361 1 COMe 2-iPr-Phenyl 362 2 COMe 2-iPr-Phenyl 363 3 COMe 2-iPr-Phenyl 364 1 CO₂Me 2-iPr-Phenyl 365 2 CO₂Me 2-iPr-Phenyl 366 3 CO₂Me 2-iPr-Phenyl 367 1 CO₂tBu 2-iPr-Phenyl 368 2 CO₂tBu 2-iPr-Phenyl 369 3 CO₂tBu 2-iPr-Phenyl 370 1 CONHMe 2-iPr-Phenyl 371 2 CONHMe 2-iPr-Phenyl 372 3 CONHMe 2-iPr-Phenyl 373 1 SO₂Me 2-iPr-Phenyl 374 2 SO₂Me 2-iPr-Phenyl 375 3 SO₂Me 2-iPr-Phenyl 376 1 SO₂NH₂ 2-iPr-Phenyl 377 2 SO₂NH₂ 2-iPr-Phenyl 378 3 SO₂NH₂ 2-iPr-Phenyl 379 1 H 4-iPr-Phenyl 380 2 H 4-iPr-Phenyl 381 3 H 4-iPr-Phenyl 382 1 Me 4-iPr-Phenyl 383 2 Me 4-iPr-Phenyl 384 3 Me 4-iPr-Phenyl 385 1 CH₂Ph 4-iPr-Phenyl 386 2 CH₂Ph 4-iPr-Phenyl 387 3 CH₂Ph 4-iPr-Phenyl 388 1 COMe 4-iPr-Phenyl 389 2 COMe 4-iPr-Phenyl 390 3 COMe 4-iPr-Phenyl 391 1 CO₂Me 4-iPr-Phenyl 392 2 CO₂Me 4-iPr-Phenyl 393 3 CO₂Me 4-iPr-Phenyl 394 1 CO₂tBu 4-iPr-Phenyl 395 2 CO₂tBu 4-iPr-Phenyl 396 3 CO₂tBu 4-iPr-Phenyl 397 1 CONHMe 4-iPr-Phenyl 398 2 CONHMe 4-iPr-Phenyl 399 3 CONHMe 4-iPr-Phenyl 400 1 SO₂Me 4-iPr-Phenyl 401 2 SO₂Me 4-iPr-Phenyl 402 3 SO₂Me 4-iPr-Phenyl 403 1 SO₂NH₂ 4-iPr-Phenyl 404 2 SO₂NH₂ 4-iPr-Phenyl 405 3 SO₂NH₂ 4-iPr-Phenyl 406 1 H 3-NH₂-Phenyl 407 2 H 3-NH₂-Phenyl 408 3 H 3-NH₂-Phenyl 409 1 Me 3-NH₂-Phenyl 410 2 Me 3-NH₂-Phenyl 411 3 Me 3-NH₂-Phenyl 412 1 CH₂Ph 3-NH₂-Phenyl 413 2 CH₂Ph 3-NH₂-Phenyl 414 3 CH₂Ph 3-NH₂-Phenyl 415 1 COMe 3-NH₂-Phenyl 416 2 COMe 3-NH₂-Phenyl 417 3 COMe 3-NH₂-Phenyl 418 1 CO₂Me 3-NH₂-Phenyl 419 2 CO₂Me 3-NH₂-Phenyl 420 3 CO₂Me 3-NH₂-Phenyl 421 1 CO₂tBu 3-NH₂-Phenyl 422 2 CO₂tBu 3-NH₂-Phenyl 423 3 CO₂tBu 3-NH₂-Phenyl 424 1 CONHMe 3-NH₂-Phenyl 425 2 CONHMe 3-NH₂-Phenyl 426 3 CONHMe 3-NH₂-Phenyl 427 1 SO₂Me 3-NH₂-Phenyl 428 2 SO₂Me 3-NH₂-Phenyl 429 3 SO₂Me 3-NH₂-Phenyl 430 1 SO₂NH₂ 3-NH₂-Phenyl 431 2 SO₂NH₂ 3-NH₂-Phenyl 432 3 SO₂NH₂ 3-NH₂-Phenyl 433 1 H 2,4-di-Me-Phenyl 434 2 H 2,4-di-Me-Phenyl 435 3 H 2,4-di-Me-Phenyl 436 1 Me 2,4-di-Me-Phenyl 437 2 Me 2,4-di-Me-Phenyl 438 3 Me 2,4-di-Me-Phenyl 439 1 CH₂Ph 2,4-di-Me-Phenyl 440 2 CH₂Ph 2,4-di-Me-Phenyl 441 3 CH₂Ph 2,4-di-Me-Phenyl 442 1 COMe 2,4-di-Me-Phenyl 443 2 COMe 2,4-di-Me-Phenyl 444 3 COMe 2,4-di-Me-Phenyl 445 1 CO₂Me 2,4-di-Me-Phenyl 446 2 CO₂Me 2,4-di-Me-Phenyl 447 3 CO₂Me 2,4-di-Me-Phenyl 448 1 CO₂tBu 2,4-di-Me-Phenyl 449 2 CO₂tBu 2,4-di-Me-Phenyl 450 3 CO₂tBu 2,4-di-Me-Phenyl 451 1 CONHMe 2,4-di-Me-Phenyl 452 2 CONHMe 2,4-di-Me-Phenyl 453 3 CONHMe 2,4-di-Me-Phenyl 454 1 SO₂Me 2,4-di-Me-Phenyl 455 2 SO₂Me 2,4-di-Me-Phenyl 456 3 SO₂Me 2,4-di-Me-Phenyl 457 1 SO₂NH₂ 2,4-di-Me-Phenyl 458 2 SO₂NH₂ 2,4-di-Me-Phenyl 459 3 SO₂NH₂ 2,4-di-Me-Phenyl 460 1 H 2,6-di-iPr-Phenyl 461 2 H 2,6-di-iPr-Phenyl 462 3 H 2,6-di-iPr-Phenyl 463 1 Me 2,6-di-iPr-Phenyl 464 2 Me 2,6-di-iPr-Phenyl 465 3 Me 2,6-di-iPr-Phenyl 466 1 CH₂Ph 2,6-di-iPr-Phenyl 467 2 CH₂Ph 2,6-di-iPr-Phenyl 468 3 CH₂Ph 2,6-di-iPr-Phenyl 469 1 COMe 2,6-di-iPr-Phenyl 470 2 COMe 2,6-di-iPr-Phenyl 471 3 COMe 2,6-di-iPr-Phenyl 472 1 CO₂Me 2,6-di-iPr-Phenyl 473 2 CO₂Me 2,6-di-iPr-Phenyl 474 3 CO₂Me 2,6-di-iPr-Phenyl 475 1 CO₂tBu 2,6-di-iPr-Phenyl 476 2 CO₂tBu 2,6-di-iPr-Phenyl 477 3 CO₂tBu 2,6-di-iPr-Phenyl 478 1 CONHMe 2,6-di-iPr-Phenyl 479 2 CONHMe 2,6-di-iPr-Phenyl 480 3 CONHMe 2,6-di-iPr-Phenyl 481 1 SO₂Me 2,6-di-iPr-Phenyl 482 2 SO₂Me 2,6-di-iPr-Phenyl 483 3 SO₂Me 2,6-di-iPr-Phenyl 484 1 SO₂NH₂ 2,6-di-iPr-Phenyl 485 2 SO₂NH₂ 2,6-di-iPr-Phenyl 486 3 SO₂NH₂ 2,6-di-iPr-Phenyl 487 1 H 3-Ph-Phenyl 488 2 H 3-Ph-Phenyl 489 3 H 3-Ph-Phenyl 490 1 Me 3-Ph-Phenyl 491 2 Me 3-Ph-Phenyl 492 3 Me 3-Ph-Phenyl 493 1 CH₂Ph 3-Ph-Phenyl 494 2 CH₂Ph 3-Ph-Phenyl 495 3 CH₂Ph 3-Ph-Phenyl 496 1 COMe 3-Ph-Phenyl 497 2 COMe 3-Ph-Phenyl 498 3 COMe 3-Ph-Phenyl 499 1 CO₂Me 3-Ph-Phenyl 500 2 CO₂Me 3-Ph-Phenyl 501 3 CO₂Me 3-Ph-Phenyl 502 1 CO₂tBu 3-Ph-Phenyl 503 2 CO₂tBu 3-Ph-Phenyl 504 3 CO₂tBu 3-Ph-Phenyl 505 1 CONHMe 3-Ph-Phenyl 506 2 CONHMe 3-Ph-Phenyl 507 3 CONHMe 3-Ph-Phenyl 508 1 SO₂Me 3-Ph-Phenyl 509 2 SO₂Me 3-Ph-Phenyl 510 3 SO₂Me 3-Ph-Phenyl 511 1 SO₂NH₂ 3-Ph-Phenyl 512 2 SO₂NH₂ 3-Ph-Phenyl 513 3 SO₂NH₂ 3-Ph-Phenyl 514 1 H 2-morpholino-phenyl 515 2 H 2-morpholino-phenyl 516 3 H 2-morpholino-phenyl 517 1 Me 2-morpholino-phenyl 518 2 Me 2-morpholino-phenyl 519 3 Me 2-morpholino-phenyl 520 1 CH₂Ph 2-morpholino-phenyl 521 2 CH₂Ph 2-morpholino-phenyl 522 3 CH₂Ph 2-morpholino-phenyl 523 1 COMe 2-morpholino-phenyl 524 2 COMe 2-morpholino-phenyl 525 3 COMe 2-morpholino-phenyl 526 1 CO₂Me 2-morpholino-phenyl 527 2 CO₂Me 2-morpholino-phenyl 528 3 CO₂Me 2-morpholino-phenyl 529 1 CO₂tBu 2-morpholino-phenyl 530 2 CO₂tBu 2-morpholino-phenyl 531 3 CO₂tBu 2-morpholino-phenyl 532 1 CONHMe 2-morpholino-phenyl 533 2 CONHMe 2-morpholino-phenyl 534 3 CONHMe 2-morpholino-phenyl 535 1 SO₂Me 2-morpholino-phenyl 536 2 SO₂Me 2-morpholino-phenyl 537 3 SO₂Me 2-morpholino-phenyl 538 1 SO₂NH₂ 2-morpholino-phenyl 539 2 SO₂NH₂ 2-morpholino-phenyl 540 3 SO₂NH₂ 2-morpholino-phenyl 541 1 H 4-morpholino-phenyl 542 2 H 4-morpholino-phenyl 543 3 H 4-morpholino-phenyl 544 1 Me 4-morpholino-phenyl 545 2 Me 4-morpholino-phenyl 546 3 Me 4-morpholino-phenyl 547 1 CH₂Ph 4-morpholino-phenyl 548 2 CH₂Ph 4-morpholino-phenyl 549 3 CH₂Ph 4-morpholino-phenyl 550 1 COMe 4-morpholino-phenyl 551 2 COMe 4-morpholino-phenyl 552 3 COMe 4-morpholino-phenyl 553 1 CO₂Me 4-morpholino-phenyl 554 2 CO₂Me 4-morpholino-phenyl 555 3 CO₂Me 4-morpholino-phenyl 556 1 CO₂tBu 4-morpholino-phenyl 557 2 CO₂tBu 4-morpholino-phenyl 558 3 CO₂tBu 4-morpholino-phenyl 559 1 CONHMe 4-morpholino-phenyl 560 2 CONHMe 4-morpholino-phenyl 561 3 CONHMe 4-morpholino-phenyl 562 1 SO₂Me 4-morpholino-phenyl 563 2 SO₂Me 4-morpholino-phenyl 564 3 SO₂Me 4-morpholino-phenyl 565 1 SO₂NH₂ 4-morpholino-phenyl 566 2 SO₂NH₂ 4-morpholino-phenyl 567 3 SO₂NH₂ 4-morpholino-phenyl 568 1 H 2-pyrimidinyl 569 2 H 2-pyrimidinyl 570 3 H 2-pyrimidinyl 571 1 Me 2-pyrimidinyl 572 2 Me 2-pyrimidinyl 573 3 Me 2-pyrimidinyl 574 1 CH₂Ph 2-pyrimidinyl 575 2 CH₂Ph 2-pyrimidinyl 576 3 CH₂Ph 2-pyrimidinyl 577 1 COMe 2-pyrimidinyl 578 2 COMe 2-pyrimidinyl 579 3 COMe 2-pyrimidinyl 580 1 CO₂Me 2-pyrimidinyl 581 2 CO₂Me 2-pyrimidinyl 582 3 CO₂Me 2-pyrimidinyl 583 1 CO₂tBu 2-pyrimidinyl 584 2 CO₂tBu 2-pyrimidinyl 585 3 CO₂tBu 2-pyrimidinyl 586 1 CONHMe 2-pyrimidinyl 587 2 CONHMe 2-pyrimidinyl 588 3 CONHMe 2-pyrimidinyl 589 1 SO₂Me 2-pyrimidinyl 590 2 SO₂Me 2-pyrimidinyl 591 3 SO₂Me 2-pyrimidinyl 592 1 SO₂NH₂ 2-pyrimidinyl 593 2 SO₂NH₂ 2-pyrimidinyl 594 3 SO₂NH₂ 2-pyrimidinyl 595 1 H 2-methyl-1H- benzo[d]imidazol-4-yl 596 2 H 2-methyl-1H- benzo[d]imidazol-4-yl 597 3 H 2-methyl-1H- benzo[d]imidazol-4-yl 598 1 Me 2-methyl-1H- benzo[d]imidazol-4-yl 599 2 Me 2-methyl-1H- benzo[d]imidazol-4-yl 600 3 Me 2-methyl-1H- benzo[d]imidazol-4-yl 601 1 CH₂Ph 2-methyl-1H- benzo[d]imidazol-4-yl 602 2 CH₂Ph 2-methyl-1H- benzo[d]imidazol-4-yl 603 3 CH₂Ph 2-methyl-1H- benzo[d]imidazol-4-yl 604 1 COMe 2-methyl-1H- benzo[d]imidazol-4-yl 605 2 COMe 2-methyl-1H- benzo[d]imidazol-4-yl 606 3 COMe 2-methyl-1H- benzo[d]imidazol-4-yl 607 1 CO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 608 2 CO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 609 3 CO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 610 1 CO₂tBu 2-methyl-1H- benzo[d]imidazol-4-yl 611 2 CO₂tBu 2-methyl-1H- benzo[d]imidazol-4-yl 612 3 CO₂tBu 2-methyl-1H- benzo[d]imidazol-4-yl 613 1 CONHMe 2-methyl-1H- benzo[d]imidazol-4-yl 614 2 CONHMe 2-methyl-1H- benzo[d]imidazol-4-yl 615 3 CONHMe 2-methyl-1H- benzo[d]imidazol-4-yl 616 1 SO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 617 2 SO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 618 3 SO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 619 1 SO₂NH₂ 2-methyl-1H- benzo[d]imidazol-4-yl 620 2 SO₂NH₂ 2-methyl-1H- benzo[d]imidazol-4-yl 621 3 SO₂NH₂ 2-methyl-1H- benzo[d]imidazol-4-yl 622 1 H 4-OH-Phenyl 623 2 H 4-OH-Phenyl 624 3 H 4-OH-Phenyl 625 1 Me 4-OH-Phenyl 626 2 Me 4-OH-Phenyl 627 3 Me 4-OH-Phenyl 628 1 CH₂Ph 4-OH-Phenyl 629 2 CH₂Ph 4-OH-Phenyl 630 3 CH₂Ph 4-OH-Phenyl 631 1 COMe 4-OH-Phenyl 632 2 COMe 4-OH-Phenyl 633 3 COMe 4-OH-Phenyl 634 1 CO₂Me 4-OH-Phenyl 635 2 CO₂Me 4-OH-Phenyl 636 3 CO₂Me 4-OH-Phenyl 637 1 CO₂tBu 4-OH-Phenyl 638 2 CO₂tBu 4-OH-Phenyl 639 3 CO₂tBu 4-OH-Phenyl 640 1 CONHMe 4-OH-Phenyl 641 2 CONHMe 4-OH-Phenyl 642 3 CONHMe 4-OH-Phenyl 643 1 SO₂Me 4-OH-Phenyl 644 2 SO₂Me 4-OH-Phenyl 645 3 SO₂Me 4-OH-Phenyl 646 1 SO₂NH₂ 4-OH-Phenyl 647 2 SO₂NH₂ 4-OH-Phenyl 648 3 SO₂NH₂ 4-OH-Phenyl 649 1 H 2-OH-Phenyl 650 2 H 2-OH-Phenyl 651 3 H 2-OH-Phenyl 652 1 Me 2-OH-Phenyl 653 2 Me 2-OH-Phenyl 654 3 Me 2-OH-Phenyl 655 1 CH₂Ph 2-OH-Phenyl 656 2 CH₂Ph 2-OH-Phenyl 657 3 CH₂Ph 2-OH-Phenyl 658 1 COMe 2-OH-Phenyl 659 2 COMe 2-OH-Phenyl 660 3 COMe 2-OH-Phenyl 661 1 CO₂Me 2-OH-Phenyl 662 2 CO₂Me 2-OH-Phenyl 663 3 CO₂Me 2-OH-Phenyl 664 1 CO₂tBu 2-OH-Phenyl 665 2 CO₂tBu 2-OH-Phenyl 666 3 CO₂tBu 2-OH-Phenyl 667 1 CONHMe 2-OH-Phenyl 668 2 CONHMe 2-OH-Phenyl 669 3 CONHMe 2-OH-Phenyl 670 1 SO₂Me 2-OH-Phenyl 671 2 SO₂Me 2-OH-Phenyl 672 3 SO₂Me 2-OH-Phenyl 673 1 SO₂NH₂ 2-OH-Phenyl 674 2 SO₂NH₂ 2-OH-Phenyl 675 3 SO₂NH₂ 2-OH-Phenyl 676 1 H 4-OMe-Phenyl 677 2 H 4-OMe-Phenyl 678 3 H 4-OMe-Phenyl 679 1 Me 4-OMe-Phenyl 680 2 Me 4-OMe-Phenyl 681 3 Me 4-OMe-Phenyl 682 1 CH₂Ph 4-OMe-Phenyl 683 2 CH₂Ph 4-OMe-Phenyl 684 3 CH₂Ph 4-OMe-Phenyl 685 1 COMe 4-OMe-Phenyl 686 2 COMe 4-OMe-Phenyl 687 3 COMe 4-OMe-Phenyl 688 1 CO₂Me 4-OMe-Phenyl 689 2 CO₂Me 4-OMe-Phenyl 690 3 CO₂Me 4-OMe-Phenyl 691 1 CO₂tBu 4-OMe-Phenyl 692 2 CO₂tBu 4-OMe-Phenyl 693 3 CO₂tBu 4-OMe-Phenyl 694 1 CONHMe 4-OMe-Phenyl 695 2 CONHMe 4-OMe-Phenyl 696 3 CONHMe 4-OMe-Phenyl 697 1 SO₂Me 4-OMe-Phenyl 698 2 SO₂Me 4-OMe-Phenyl 699 3 SO₂Me 4-OMe-Phenyl 700 1 SO₂NH₂ 4-OMe-Phenyl 701 2 SO₂NH₂ 4-OMe-Phenyl 702 3 SO₂NH₂ 4-OMe-Phenyl 703 1 H 2-OMe-Phenyl 704 2 H 2-OMe-Phenyl 705 3 H 2-OMe-Phenyl 706 1 Me 2-OMe-Phenyl 707 2 Me 2-OMe-Phenyl 708 3 Me 2-OMe-Phenyl 709 1 CH₂Ph 2-OMe-Phenyl 710 2 CH₂Ph 2-OMe-Phenyl 711 3 CH₂Ph 2-OMe-Phenyl 712 1 COMe 2-OMe-Phenyl 713 2 COMe 2-OMe-Phenyl 714 3 COMe 2-OMe-Phenyl 715 1 CO₂Me 2-OMe-Phenyl 716 2 CO₂Me 2-OMe-Phenyl 717 3 CO₂Me 2-OMe-Phenyl 718 1 CO₂tBu 2-OMe-Phenyl 719 2 CO₂tBu 2-OMe-Phenyl 720 3 CO₂tBu 2-OMe-Phenyl 721 1 CONHMe 2-OMe-Phenyl 722 2 CONHMe 2-OMe-Phenyl 723 3 CONHMe 2-OMe-Phenyl 724 1 SO₂Me 2-OMe-Phenyl 725 2 SO₂Me 2-OMe-Phenyl 726 3 SO₂Me 2-OMe-Phenyl 727 1 SO₂NH₂ 2-OMe-Phenyl 728 2 SO₂NH₂ 2-OMe-Phenyl 729 3 SO₂NH₂ 2-OMe-Phenyl 730 1 H 3-CN-Phenyl 731 2 H 3-CN-Phenyl 732 3 H 3-CN-Phenyl 733 1 Me 3-CN-Phenyl 734 2 Me 3-CN-Phenyl 735 3 Me 3-CN-Phenyl 736 1 CH₂Ph 3-CN-Phenyl 737 2 CH₂Ph 3-CN-Phenyl 738 3 CH₂Ph 3-CN-Phenyl 739 1 COMe 3-CN-Phenyl 740 2 COMe 3-CN-Phenyl 741 3 COMe 3-CN-Phenyl 742 1 CO₂Me 3-CN-Phenyl 743 2 CO₂Me 3-CN-Phenyl 744 3 CO₂Me 3-CN-Phenyl 745 1 CO₂tBu 3-CN-Phenyl 746 2 CO₂tBu 3-CN-Phenyl 747 3 CO₂tBu 3-CN-Phenyl 748 1 CONHMe 3-CN-Phenyl 749 2 CONHMe 3-CN-Phenyl 750 3 CONHMe 3-CN-Phenyl 751 1 SO₂Me 3-CN-Phenyl 752 2 SO₂Me 3-CN-Phenyl 753 3 SO₂Me 3-CN-Phenyl 754 1 SO₂NH₂ 3-CN-Phenyl 755 2 SO₂NH₂ 3-CN-Phenyl 756 3 SO₂NH₂ 3-CN-Phenyl 757 1 H 2-Me-Phenyl 758 2 H 2-Me-Phenyl 759 3 H 2-Me-Phenyl 760 1 Me 2-Me-Phenyl 761 2 Me 2-Me-Phenyl 762 3 Me 2-Me-Phenyl 763 1 CH₂Ph 2-Me-Phenyl 764 2 CH₂Ph 2-Me-Phenyl 765 3 CH₂Ph 2-Me-Phenyl 766 1 COMe 2-Me-Phenyl 767 2 COMe 2-Me-Phenyl 768 3 COMe 2-Me-Phenyl 769 1 CO₂Me 2-Me-Phenyl 770 2 CO₂Me 2-Me-Phenyl 771 3 CO₂Me 2-Me-Phenyl 772 1 CO₂tBu 2-Me-Phenyl 773 2 CO₂tBu 2-Me-Phenyl 774 3 CO₂tBu 2-Me-Phenyl 775 1 CONHMe 2-Me-Phenyl 776 2 CONHMe 2-Me-Phenyl 777 3 CONHMe 2-Me-Phenyl 778 1 SO₂Me 2-Me-Phenyl 779 2 SO₂Me 2-Me-Phenyl 780 3 SO₂Me 2-Me-Phenyl 781 1 SO₂NH₂ 2-Me-Phenyl 782 2 SO₂NH₂ 2-Me-Phenyl 783 3 SO₂NH₂ 2-Me-Phenyl 784 1 H 4-Me-Phenyl 785 2 H 4-Me-Phenyl 786 3 H 4-Me-Phenyl 787 1 Me 4-Me-Phenyl 788 2 Me 4-Me-Phenyl 789 3 Me 4-Me-Phenyl 790 1 CH₂Ph 4-Me-Phenyl 791 2 CH₂Ph 4-Me-Phenyl 792 3 CH₂Ph 4-Me-Phenyl 793 1 COMe 4-Me-Phenyl 794 2 COMe 4-Me-Phenyl 795 3 COMe 4-Me-Phenyl 796 1 CO₂Me 4-Me-Phenyl 797 2 CO₂Me 4-Me-Phenyl 798 3 CO₂Me 4-Me-Phenyl 799 1 CO₂tBu 4-Me-Phenyl 800 2 CO₂tBu 4-Me-Phenyl 801 3 CO₂tBu 4-Me-Phenyl 802 1 CONHMe 4-Me-Phenyl 803 2 CONHMe 4-Me-Phenyl 804 3 CONHMe 4-Me-Phenyl 805 1 SO₂Me 4-Me-Phenyl 806 2 SO₂Me 4-Me-Phenyl 807 3 SO₂Me 4-Me-Phenyl 808 1 SO₂NH₂ 4-Me-Phenyl 809 2 SO₂NH₂ 4-Me-Phenyl 810 3 SO₂NH₂ 4-Me-Phenyl 811 1 H 3-F-Phenyl 812 2 H 3-F-Phenyl 813 3 H 3-F-Phenyl 814 1 Me 3-F-Phenyl 815 2 Me 3-F-Phenyl 816 3 Me 3-F-Phenyl 817 1 CH₂Ph 3-F-Phenyl 818 2 CH₂Ph 3-F-Phenyl 819 3 CH₂Ph 3-F-Phenyl 820 1 COMe 3-F-Phenyl 821 2 COMe 3-F-Phenyl 822 3 COMe 3-F-Phenyl 823 1 CO₂Me 3-F-Phenyl 824 2 CO₂Me 3-F-Phenyl 825 3 CO₂Me 3-F-Phenyl 826 1 CO₂tBu 3-F-Phenyl 827 2 CO₂tBu 3-F-Phenyl 828 3 CO₂tBu 3-F-Phenyl 829 1 CONHMe 3-F-Phenyl 830 2 CONHMe 3-F-Phenyl 831 3 CONHMe 3-F-Phenyl 832 1 SO₂Me 3-F-Phenyl 833 2 SO₂Me 3-F-Phenyl 834 3 SO₂Me 3-F-Phenyl 835 1 SO₂NH₂ 3-F-Phenyl 836 2 SO₂NH₂ 3-F-Phenyl 837 3 SO₂NH₂ 3-F-Phenyl 838 1 H 2-Cl-Phenyl 839 2 H 2-Cl-Phenyl 840 3 H 2-Cl-Phenyl 841 1 Me 2-Cl-Phenyl 842 2 Me 2-Cl-Phenyl 843 3 Me 2-Cl-Phenyl 844 1 CH₂Ph 2-Cl-Phenyl 845 2 CH₂Ph 2-Cl-Phenyl 846 3 CH₂Ph 2-Cl-Phenyl 847 1 COMe 2-Cl-Phenyl 848 2 COMe 2-Cl-Phenyl 849 3 COMe 2-Cl-Phenyl 850 1 CO₂Me 2-Cl-Phenyl 851 2 CO₂Me 2-Cl-Phenyl 852 3 CO₂Me 2-Cl-Phenyl 853 1 CO₂tBu 2-Cl-Phenyl 854 2 CO₂tBu 2-Cl-Phenyl 855 3 CO₂tBu 2-Cl-Phenyl 856 1 CONHMe 2-Cl-Phenyl 857 2 CONHMe 2-Cl-Phenyl 858 3 CONHMe 2-Cl-Phenyl 859 1 SO₂Me 2-Cl-Phenyl 860 2 SO₂Me 2-Cl-Phenyl 861 3 SO₂Me 2-Cl-Phenyl 862 1 SO₂NH₂ 2-Cl-Phenyl 863 2 SO₂NH₂ 2-Cl-Phenyl 864 3 SO₂NH₂ 2-Cl-Phenyl 865 1 H 4-Cl-Phenyl 866 2 H 4-Cl-Phenyl 867 3 H 4-Cl-Phenyl 868 1 Me 4-Cl-Phenyl 869 2 Me 4-Cl-Phenyl 870 3 Me 4-Cl-Phenyl 871 1 CH₂Ph 4-Cl-Phenyl 872 2 CH₂Ph 4-Cl-Phenyl 873 3 CH₂Ph 4-Cl-Phenyl 874 1 COMe 4-Cl-Phenyl 875 2 COMe 4-Cl-Phenyl 876 3 COMe 4-Cl-Phenyl 877 1 CO₂Me 4-Cl-Phenyl 878 2 CO₂Me 4-Cl-Phenyl 879 3 CO₂Me 4-Cl-Phenyl 880 1 CO₂tBu 4-Cl-Phenyl 881 2 CO₂tBu 4-Cl-Phenyl 882 3 CO₂tBu 4-Cl-Phenyl 883 1 CONHMe 4-Cl-Phenyl 884 2 CONHMe 4-Cl-Phenyl 885 3 CONHMe 4-Cl-Phenyl 886 1 SO₂Me 4-Cl-Phenyl 887 2 SO₂Me 4-Cl-Phenyl 888 3 SO₂Me 4-Cl-Phenyl 889 1 SO₂NH₂ 4-Cl-Phenyl 890 2 SO₂NH₂ 4-Cl-Phenyl 891 3 SO₂NH₂ 4-Cl-Phenyl 892 1 H 3-Br-Phenyl 893 2 H 3-Br-Phenyl 894 3 H 3-Br-Phenyl 895 1 Me 3-Br-Phenyl 896 2 Me 3-Br-Phenyl 897 3 Me 3-Br-Phenyl 898 1 CH₂Ph 3-Br-Phenyl 899 2 CH₂Ph 3-Br-Phenyl 900 3 CH₂Ph 3-Br-Phenyl 901 1 COMe 3-Br-Phenyl 902 2 COMe 3-Br-Phenyl 903 3 COMe 3-Br-Phenyl 904 1 CO₂Me 3-Br-Phenyl 905 2 CO₂Me 3-Br-Phenyl 906 3 CO₂Me 3-Br-Phenyl 907 1 CO₂tBu 3-Br-Phenyl 908 2 CO₂tBu 3-Br-Phenyl 909 3 CO₂tBu 3-Br-Phenyl 910 1 CONHMe 3-Br-Phenyl 911 2 CONHMe 3-Br-Phenyl 912 3 CONHMe 3-Br-Phenyl 913 1 SO₂Me 3-Br-Phenyl 914 2 SO₂Me 3-Br-Phenyl 915 3 SO₂Me 3-Br-Phenyl 916 1 SO₂NH₂ 3-Br-Phenyl 917 2 SO₂NH₂ 3-Br-Phenyl 918 3 SO₂NH₂ 3-Br-Phenyl 919 1 H 2-CF₃-Phenyl 920 2 H 2-CF₃-Phenyl 921 3 H 2-CF₃-Phenyl 922 1 Me 2-CF₃-Phenyl 923 2 Me 2-CF₃-Phenyl 924 3 Me 2-CF₃-Phenyl 925 1 CH₂Ph 2-CF₃-Phenyl 926 2 CH₂Ph 2-CF₃-Phenyl 927 3 CH₂Ph 2-CF₃-Phenyl 928 1 COMe 2-CF₃-Phenyl 929 2 COMe 2-CF₃-Phenyl 930 3 COMe 2-CF₃-Phenyl 931 1 CO₂Me 2-CF₃-Phenyl 932 2 CO₂Me 2-CF₃-Phenyl 933 3 CO₂Me 2-CF₃-Phenyl 934 1 CO₂tBu 2-CF₃-Phenyl 935 2 CO₂tBu 2-CF₃-Phenyl 936 3 CO₂tBu 2-CF₃-Phenyl 937 1 CONHMe 2-CF₃-Phenyl 938 2 CONHMe 2-CF₃-Phenyl 939 3 CONHMe 2-CF₃-Phenyl 940 1 SO₂Me 2-CF₃-Phenyl 941 2 SO₂Me 2-CF₃-Phenyl 942 3 SO₂Me 2-CF₃-Phenyl 943 1 SO₂NH₂ 2-CF₃-Phenyl 944 2 SO₂NH₂ 2-CF₃-Phenyl 945 3 SO₂NH₂ 2-CF₃-Phenyl 946 1 H 4-CF₃-Phenyl 947 2 H 4-CF₃-Phenyl 948 3 H 4-CF₃-Phenyl 949 1 Me 4-CF₃-Phenyl 950 2 Me 4-CF₃-Phenyl 951 3 Me 4-CF₃-Phenyl 952 1 CH₂Ph 4-CF₃-Phenyl 953 2 CH₂Ph 4-CF₃-Phenyl 954 3 CH₂Ph 4-CF₃-Phenyl 955 1 COMe 4-CF₃-Phenyl 956 2 COMe 4-CF₃-Phenyl 957 3 COMe 4-CF₃-Phenyl 958 1 CO₂Me 4-CF₃-Phenyl 959 2 CO₂Me 4-CF₃-Phenyl 960 3 CO₂Me 4-CF₃-Phenyl 961 1 CO₂tBu 4-CF₃-Phenyl 962 2 CO₂tBu 4-CF₃-Phenyl 963 3 CO₂tBu 4-CF₃-Phenyl 964 1 CONHMe 4-CF₃-Phenyl 965 2 CONHMe 4-CF₃-Phenyl 966 3 CONHMe 4-CF₃-Phenyl 967 1 SO₂Me 4-CF₃-Phenyl 968 2 SO₂Me 4-CF₃-Phenyl 969 3 SO₂Me 4-CF₃-Phenyl 970 1 SO₂NH₂ 4-CF₃-Phenyl 971 2 SO₂NH₂ 4-CF₃-Phenyl 972 3 SO₂NH₂ 4-CF₃-Phenyl 973 1 H 3-iPr-Phenyl 974 2 H 3-iPr-Phenyl 975 3 H 3-iPr-Phenyl 976 1 Me 3-iPr-Phenyl 977 2 Me 3-iPr-Phenyl 978 3 Me 3-iPr-Phenyl 979 1 CH₂Ph 3-iPr-Phenyl 980 2 CH₂Ph 3-iPr-Phenyl 981 3 CH₂Ph 3-iPr-Phenyl 982 1 COMe 3-iPr-Phenyl 983 2 COMe 3-iPr-Phenyl 984 3 COMe 3-iPr-Phenyl 985 1 CO₂Me 3-iPr-Phenyl 986 2 CO₂Me 3-iPr-Phenyl 987 3 CO₂Me 3-iPr-Phenyl 988 1 CO₂tBu 3-iPr-Phenyl 989 2 CO₂tBu 3-iPr-Phenyl 990 3 CO₂tBu 3-iPr-Phenyl 991 1 CONHMe 3-iPr-Phenyl 992 2 CONHMe 3-iPr-Phenyl 993 3 CONHMe 3-iPr-Phenyl 994 1 SO₂Me 3-iPr-Phenyl 995 2 SO₂Me 3-iPr-Phenyl 996 3 SO₂Me 3-iPr-Phenyl 997 1 SO₂NH₂ 3-iPr-Phenyl 998 2 SO₂NH₂ 3-iPr-Phenyl 999 3 SO₂NH₂ 3-iPr-Phenyl 1000 1 H 4-NH₂-Phenyl 1001 2 H 4-NH₂-Phenyl 1002 3 H 4-NH₂-Phenyl 1003 1 Me 4-NH₂-Phenyl 1004 2 Me 4-NH₂-Phenyl 1005 3 Me 4-NH₂-Phenyl 1006 1 CH₂Ph 4-NH₂-Phenyl 1007 2 CH₂Ph 4-NH₂-Phenyl 1008 3 CH₂Ph 4-NH₂-Phenyl 1009 1 COMe 4-NH₂-Phenyl 1010 2 COMe 4-NH₂-Phenyl 1011 3 COMe 4-NH₂-Phenyl 1012 1 CO₂Me 4-NH₂-Phenyl 1013 2 CO₂Me 4-NH₂-Phenyl 1014 3 CO₂Me 4-NH₂-Phenyl 1015 1 CO₂tBu 4-NH₂-Phenyl 1016 2 CO₂tBu 4-NH₂-Phenyl 1017 3 CO₂tBu 4-NH₂-Phenyl 1018 1 CONHMe 4-NH₂-Phenyl 1019 2 CONHMe 4-NH₂-Phenyl 1020 3 CONHMe 4-NH₂-Phenyl 1021 1 SO₂Me 4-NH₂-Phenyl 1022 2 SO₂Me 4-NH₂-Phenyl 1023 3 SO₂Me 4-NH₂-Phenyl 1024 1 SO₂NH₂ 4-NH₂-Phenyl 1025 2 SO₂NH₂ 4-NH₂-Phenyl 1026 3 SO₂NH₂ 4-NH₂-Phenyl 1027 1 H 2-NH₂-Phenyl 1028 2 H 2-NH₂-Phenyl 1029 3 H 2-NH₂-Phenyl 1030 1 Me 2-NH₂-Phenyl 1031 2 Me 2-NH₂-Phenyl 1032 3 Me 2-NH₂-Phenyl 1033 1 CH₂Ph 2-NH₂-Phenyl 1034 2 CH₂Ph 2-NH₂-Phenyl 1035 3 CH₂Ph 2-NH₂-Phenyl 1036 1 COMe 2-NH₂-Phenyl 1037 2 COMe 2-NH₂-Phenyl 1038 3 COMe 2-NH₂-Phenyl 1039 1 CO₂Me 2-NH₂-Phenyl 1040 2 CO₂Me 2-NH₂-Phenyl 1041 3 CO₂Me 2-NH₂-Phenyl 1042 1 CO₂tBu 2-NH₂-Phenyl 1043 2 CO₂tBu 2-NH₂-Phenyl 1044 3 CO₂tBu 2-NH₂-Phenyl 1045 1 CONHMe 2-NH₂-Phenyl 1046 2 CONHMe 2-NH₂-Phenyl 1047 3 CONHMe 2-NH₂-Phenyl 1048 1 SO₂Me 2-NH₂-Phenyl 1049 2 SO₂Me 2-NH₂-Phenyl 1050 3 SO₂Me 2-NH₂-Phenyl 1051 1 SO₂NH₂ 2-NH₂-Phenyl 1052 2 SO₂NH₂ 2-NH₂-Phenyl 1053 3 SO₂NH₂ 2-NH₂-Phenyl 1054 1 H 2,6-di-Me-Phenyl 1055 2 H 2,6-di-Me-Phenyl 1056 3 H 2,6-di-Me-Phenyl 1057 1 Me 2,6-di-Me-Phenyl 1058 2 Me 2,6-di-Me-Phenyl 1059 3 Me 2,6-di-Me-Phenyl 1060 1 CH₂Ph 2,6-di-Me-Phenyl 1061 2 CH₂Ph 2,6-di-Me-Phenyl 1062 3 CH₂Ph 2,6-di-Me-Phenyl 1063 1 COMe 2,6-di-Me-Phenyl 1064 2 COMe 2,6-di-Me-Phenyl 1065 3 COMe 2,6-di-Me-Phenyl 1066 1 CO₂Me 2,6-di-Me-Phenyl 1067 2 CO₂Me 2,6-di-Me-Phenyl 1068 3 CO₂Me 2,6-di-Me-Phenyl 1069 1 CO₂tBu 2,6-di-Me-Phenyl 1070 2 CO₂tBu 2,6-di-Me-Phenyl 1071 3 CO₂tBu 2,6-di-Me-Phenyl 1072 1 CONHMe 2,6-di-Me-Phenyl 1073 2 CONHMe 2,6-di-Me-Phenyl 1074 3 CONHMe 2,6-di-Me-Phenyl 1075 1 SO₂Me 2,6-di-Me-Phenyl 1076 2 SO₂Me 2,6-di-Me-Phenyl 1077 3 SO₂Me 2,6-di-Me-Phenyl 1078 1 SO₂NH₂ 2,6-di-Me-Phenyl 1079 2 SO₂NH₂ 2,6-di-Me-Phenyl 1080 3 SO₂NH₂ 2,6-di-Me-Phenyl 1081 1 H 2-Ph-Phenyl 1082 2 H 2-Ph-Phenyl 1083 3 H 2-Ph-Phenyl 1084 1 Me 2-Ph-Phenyl 1085 2 Me 2-Ph-Phenyl 1086 3 Me 2-Ph-Phenyl 1087 1 CH₂Ph 2-Ph-Phenyl 1088 2 CH₂Ph 2-Ph-Phenyl 1089 3 CH₂Ph 2-Ph-Phenyl 1090 1 COMe 2-Ph-Phenyl 1091 2 COMe 2-Ph-Phenyl 1092 3 COMe 2-Ph-Phenyl 1093 1 CO₂Me 2-Ph-Phenyl 1094 2 CO₂Me 2-Ph-Phenyl 1095 3 CO₂Me 2-Ph-Phenyl 1096 1 CO₂tBu 2-Ph-Phenyl 1097 2 CO₂tBu 2-Ph-Phenyl 1098 3 CO₂tBu 2-Ph-Phenyl 1099 1 CONHMe 2-Ph-Phenyl 1100 2 CONHMe 2-Ph-Phenyl 1101 3 CONHMe 2-Ph-Phenyl 1102 1 SO₂Me 2-Ph-Phenyl 1103 2 SO₂Me 2-Ph-Phenyl 1104 3 SO₂Me 2-Ph-Phenyl 1105 1 SO₂NH₂ 2-Ph-Phenyl 1106 2 SO₂NH₂ 2-Ph-Phenyl 1107 3 SO₂NH₂ 2-Ph-Phenyl 1108 1 H 4-Ph-Phenyl 1109 2 H 4-Ph-Phenyl 1110 3 H 4-Ph-Phenyl 1111 1 Me 4-Ph-Phenyl 1112 2 Me 4-Ph-Phenyl 1113 3 Me 4-Ph-Phenyl 1114 1 CH₂Ph 4-Ph-Phenyl 1115 2 CH₂Ph 4-Ph-Phenyl 1116 3 CH₂Ph 4-Ph-Phenyl 1117 1 COMe 4-Ph-Phenyl 1118 2 COMe 4-Ph-Phenyl 1119 3 COMe 4-Ph-Phenyl 1120 1 CO₂Me 4-Ph-Phenyl 1121 2 CO₂Me 4-Ph-Phenyl 1122 3 CO₂Me 4-Ph-Phenyl 1123 1 CO₂tBu 4-Ph-Phenyl 1124 2 CO₂tBu 4-Ph-Phenyl 1125 3 CO₂tBu 4-Ph-Phenyl 1126 1 CONHMe 4-Ph-Phenyl 1127 2 CONHMe 4-Ph-Phenyl 1128 3 CONHMe 4-Ph-Phenyl 1129 1 SO₂Me 4-Ph-Phenyl 1130 2 SO₂Me 4-Ph-Phenyl 1131 3 SO₂Me 4-Ph-Phenyl 1132 1 SO₂NH₂ 4-Ph-Phenyl 1133 2 SO₂NH₂ 4-Ph-Phenyl 1134 3 SO₂NH₂ 4-Ph-Phenyl 1135 1 H 3-morpholino-phenyl 1136 2 H 3-morpholino-phenyl 1137 3 H 3-morpholino-phenyl 1138 1 Me 3-morpholino-henyl 1139 2 Me 3-morpholino-phenyl 1140 3 Me 3-morpholino-phenyl 1141 1 CH₂Ph 3-morpholino-phenyl 1142 2 CH₂Ph 3-morpholino-phenyl 1143 3 CH₂Ph 3-morpholino-phenyl 1144 1 COMe 3-morpholino-phenyl 1145 2 COMe 3-morpholino-phenyl 1146 3 COMe 3-morpholino-phenyl 1147 1 CO₂Me 3-morpholino-phenyl 1148 2 CO₂Me 3-morpholino-phenyl 1149 3 CO₂Me 3-morpholino-phenyl 1150 1 CO₂tBu 3-morpholino-phenyl 1151 2 CO₂tBu 3-morpholino-phenyl 1152 3 CO₂tBu 3-morpholino-phenyl 1153 1 CONHMe 3-morpholino-phenyl 1154 2 CONHMe 3-morpholino-phenyl 1155 3 CONHMe 3-morpholino-phenyl 1156 1 SO₂Me 3-morpholino-phenyl 1157 2 SO₂Me 3-morpholino-phenyl 1158 3 SO₂Me 3-morpholino-phenyl 1159 1 SO₂NH₂ 3-morpholino-phenyl 1160 2 SO₂NH₂ 3-morpholino-phenyl 1161 3 SO₂NH₂ 3-morpholino-phenyl 1162 1 H 2-pyrazinyl 1163 2 H 2-pyrazinyl 1164 3 H 2-pyrazinyl 1165 1 Me 2-pyrazinyl 1166 2 Me 2-pyrazinyl 1167 3 Me 2-pyrazinyl 1168 1 CH₂Ph 2-pyrazinyl 1169 2 CH₂Ph 2-pyrazinyl 1170 3 CH₂Ph 2-pyrazinyl 1171 1 COMe 2-pyrazinyl 1172 2 COMe 2-pyrazinyl 1173 3 COMe 2-pyrazinyl 1174 1 CO₂Me 2-pyrazinyl 1175 2 CO₂Me 2-pyrazinyl 1176 3 CO₂Me 2-pyrazinyl 1177 1 CO₂tBu 2-pyrazinyl 1178 2 CO₂tBu 2-pyrazinyl 1179 3 CO₂tBu 2-pyrazinyl 1180 1 CONHMe 2-pyrazinyl 1181 2 CONHMe 2-pyrazinyl 1182 3 CONHMe 2-pyrazinyl 1183 1 SO₂Me 2-pyrazinyl 1184 2 SO₂Me 2-pyrazinyl 1185 3 SO₂Me 2-pyrazinyl 1186 1 SO₂NH₂ 2-pyrazinyl 1187 2 SO₂NH₂ 2-pyrazinyl 1188 3 SO₂NH₂ 2-pyrazinyl 1189 1 H 5-indolyl 1190 2 H 5-indolyl 1191 3 H 5-indolyl 1192 1 Me 5-indolyl 1193 2 Me 5-indolyl 1194 3 Me 5-indolyl 1195 1 CH₂Ph 5-indolyl 1196 2 CH₂Ph 5-indolyl 1197 3 CH₂Ph 5-indolyl 1198 1 COMe 5-indolyl 1199 2 COMe 5-indolyl 1200 3 COMe 5-indolyl 1201 1 CO₂Me 5-indolyl 1202 2 CO₂Me 5-indolyl 1203 3 CO₂Me 5-indolyl 1204 1 CO₂tBu 5-indolyl 1205 2 CO₂tBu 5-indolyl 1206 3 CO₂tBu 5-indolyl 1207 1 CONHMe 5-indolyl 1208 2 CONHMe 5-indolyl 1209 3 CONHMe 5-indolyl 1210 1 SO₂Me 5-indolyl 1211 2 SO₂Me 5-indolyl 1212 3 SO₂Me 5-indolyl 1213 1 SO₂NH₂ 5-indolyl 1214 2 SO₂NH₂ 5-indolyl 1215 3 SO₂NH₂ 5-indolyl 1216 1 H 1H-benzo[d]imidazol- 4-yl 1217 2 H 1H-benzo[d]imidazol- 4-yl 1218 3 H 1H-benzo[d]imidazol- 4-yl 1219 1 Me 1H-benzo[d]imidazol- 4-yl 1220 2 Me 1H-benzo[d]imidazol- 4-yl 1221 3 Me 1H-benzo[d]imidazol- 4-yl 1222 1 CH₂Ph 1H-benzo[d]imidazol- 4-yl 1223 2 CH₂Ph 1H-benzo[d]imidazol- 4-yl 1224 3 CH₂Ph 1H-benzo[d]imidazol- 4-yl 1225 1 COMe 1H-benzo[d]imidazol- 4-yl 1226 2 COMe 1H-benzo[d]imidazol- 4-yl 1227 3 COMe 1H-benzo[d]imidazol- 4-yl 1228 1 CO₂Me 1H-benzo[d]imidazol- 4-yl 1229 2 CO₂Me 1H-benzo[d]imidazol- 4-yl 1230 3 CO₂Me 1H-benzo[d]imidazol- 4-yl 1231 1 CO₂tBu 1H-benzo[d]imidazol- 4-yl 1232 2 CO₂tBu 1H-benzo[d]imidazol- 4-yl 1233 3 CO₂tBu 1H-benzo[d]imidazol- 4-yl 1234 1 CONHMe 1H-benzo[d]imidazol- 4-yl 1235 2 CONHMe 1H-benzo[d]imidazol- 4-yl 1236 3 CONHMe 1H-benzo[d]imidazol- 4-yl 1237 1 SO₂Me 1H-benzo[d]imidazol- 4-yl 1238 2 SO₂Me 1H-benzo[d]imidazol- 4-yl 1239 3 SO₂Me 1H-benzo[d]imidazol- 4-yl 1240 1 SO₂NH₂ 1H-benzo[d]imidazol- 4-yl 1241 2 SO₂NH₂ 1H-benzo[d]imidazol- 4-yl 1242 3 SO₂NH₂ 1H-benzo[d]imidazol- 4-yl

Exemplary embodiments include compounds having the formula (XVIII)

or a pharmaceutically acceptable salt form thereof defined herein below in Table 2.

TABLE 2 Entry n R R³ 1 1 H Phenyl 2 2 H Phenyl 3 3 H Phenyl 4 1 Me Phenyl 5 2 Me Phenyl 6 3 Me Phenyl 7 1 CH₂Ph Phenyl 8 2 CH₂Ph Phenyl 9 3 CH₂Ph Phenyl 10 1 COMe Phenyl 11 2 COMe Phenyl 12 3 COMe Phenyl 13 1 CO₂Me Phenyl 14 2 CO₂Me Phenyl 15 3 CO₂Me Phenyl 16 1 CO₂tBu Phenyl 17 2 CO₂tBu Phenyl 18 3 CO₂tBu Phenyl 19 1 CONHMe Phenyl 20 2 CONHMe Phenyl 21 3 CONHMe Phenyl 22 1 SO₂Me Phenyl 23 2 SO₂Me Phenyl 24 3 SO₂Me Phenyl 25 1 SO₂NH₂ Phenyl 26 2 SO₂NH₂ Phenyl 27 3 SO₂NH₂ Phenyl 28 1 H 3-OH-Phenyl 29 2 H 3-OH-Phenyl 30 3 H 3-OH-Phenyl 31 1 Me 3-OH-Phenyl 32 2 Me 3-OH-Phenyl 33 3 Me 3-OH-Phenyl 34 1 CH₂Ph 3-OH-Phenyl 35 2 CH₂Ph 3-OH-Phenyl 36 3 CH₂Ph 3-OH-Phenyl 37 1 COMe 3-OH-Phenyl 38 2 COMe 3-OH-Phenyl 39 3 COMe 3-OH-Phenyl 40 1 CO₂Me 3-OH-Phenyl 41 2 CO₂Me 3-OH-Phenyl 42 3 CO₂Me 3-OH-Phenyl 43 1 CO₂tBu 3-OH-Phenyl 44 2 CO₂tBu 3-OH-Phenyl 45 3 CO₂tBu 3-OH-Phenyl 46 1 CONHMe 3-OH-Phenyl 47 2 CONHMe 3-OH-Phenyl 48 3 CONHMe 3-OH-Phenyl 49 1 SO₂Me 3-OH-Phenyl 50 2 SO₂Me 3-OH-Phenyl 51 3 SO₂Me 3-OH-Phenyl 52 1 SO₂NH₂ 3-OH-Phenyl 53 2 SO₂NH₂ 3-OH-Phenyl 54 3 SO₂NH₂ 3-OH-Phenyl 55 1 H 4-NO₂-Phenyl 56 2 H 4-NO₂-Phenyl 57 3 H 4-NO₂-Phenyl 58 1 Me 4-NO₂-Phenyl 59 2 Me 4-NO₂-Phenyl 60 3 Me 4-NO₂-Phenyl 61 1 CH₂Ph 4-NO₂-Phenyl 62 2 CH₂Ph 4-NO₂-Phenyl 63 3 CH₂Ph 4-NO₂-Phenyl 64 1 COMe 4-NO₂-Phenyl 65 2 COMe 4-NO₂-Phenyl 66 3 COMe 4-NO₂-Phenyl 67 1 CO₂Me 4-NO₂-Phenyl 68 2 CO₂Me 4-NO₂-Phenyl 69 3 CO₂Me 4-NO₂-Phenyl 70 1 CO₂tBu 4-NO₂-Phenyl 71 2 CO₂tBu 4-NO₂-Phenyl 72 3 CO₂tBu 4-NO₂-Phenyl 73 1 CONHMe 4-NO₂-Phenyl 74 2 CONHMe 4-NO₂-Phenyl 75 3 CONHMe 4-NO₂-Phenyl 76 1 SO₂Me 4-NO₂-Phenyl 77 2 SO₂Me 4-NO₂-Phenyl 78 3 SO₂Me 4-NO₂-Phenyl 79 1 SO₂NH₂ 4-NO₂-Phenyl 80 2 SO₂NH₂ 4-NO₂-Phenyl 81 3 SO₂NH₂ 4-NO₂-Phenyl 82 1 H 3-OMe-Phenyl 83 2 H 3-OMe-Phenyl 84 3 H 3-OMe-Phenyl 85 1 Me 3-OMe-Phenyl 86 2 Me 3-OMe-Phenyl 87 3 Me 3-OMe-Phenyl 88 1 CH₂Ph 3-OMe-Phenyl 89 2 CH₂Ph 3-OMe-Phenyl 90 3 CH₂Ph 3-OMe-Phenyl 91 1 COMe 3-OMe-Phenyl 92 2 COMe 3-OMe-Phenyl 93 3 COMe 3-OMe-Phenyl 94 1 CO₂Me 3-OMe-Phenyl 95 2 CO₂Me 3-OMe-Phenyl 96 3 CO₂Me 3-OMe-Phenyl 97 1 CO₂tBu 3-OMe-Phenyl 98 2 CO₂tBu 3-OMe-Phenyl 99 3 CO₂tBu 3-OMe-Phenyl 100 1 CONHMe 3-OMe-Phenyl 101 2 CONHMe 3-OMe-Phenyl 102 3 CONHMe 3-OMe-Phenyl 103 1 SO₂Me 3-OMe-Phenyl 104 2 SO₂Me 3-OMe-Phenyl 105 3 SO₂Me 3-OMe-Phenyl 106 1 SO₂NH₂ 3-OMe-Phenyl 107 2 SO₂NH₂ 3-OMe-Phenyl 108 3 SO₂NH₂ 3-OMe-Phenyl 109 1 H 4-CN-Phenyl 110 2 H 4-CN-Phenyl 111 3 H 4-CN-Phenyl 112 1 Me 4-CN-Phenyl 113 2 Me 4-CN-Phenyl 114 3 Me 4-CN-Phenyl 115 1 CH₂Ph 4-CN-Phenyl 116 2 CH₂Ph 4-CN-Phenyl 117 3 CH₂Ph 4-CN-Phenyl 118 1 COMe 4-CN-Phenyl 119 2 COMe 4-CN-Phenyl 120 3 COMe 4-CN-Phenyl 121 1 CO₂Me 4-CN-Phenyl 122 2 CO₂Me 4-CN-Phenyl 123 3 CO₂Me 4-CN-Phenyl 124 1 CO₂tBu 4-CN-Phenyl 125 2 CO₂tBu 4-CN-Phenyl 126 3 CO₂tBu 4-CN-Phenyl 127 1 CONHMe 4-CN-Phenyl 128 2 CONHMe 4-CN-Phenyl 129 3 CONHMe 4-CN-Phenyl 130 1 SO₂Me 4-CN-Phenyl 131 2 SO₂Me 4-CN-Phenyl 132 3 SO₂Me 4-CN-Phenyl 133 1 SO₂NH₂ 4-CN-Phenyl 134 2 SO₂NH₂ 4-CN-Phenyl 135 3 SO₂NH₂ 4-CN-Phenyl 136 1 H 2-CN-Phenyl 137 2 H 2-CN-Phenyl 138 3 H 2-CN-Phenyl 139 1 Me 2-CN-Phenyl 140 2 Me 2-CN-Phenyl 141 3 Me 2-CN-Phenyl 142 1 CH₂Ph 2-CN-Phenyl 143 2 CH₂Ph 2-CN-Phenyl 144 3 CH₂Ph 2-CN-Phenyl 145 1 COMe 2-CN-Phenyl 146 2 COMe 2-CN-Phenyl 147 3 COMe 2-CN-Phenyl 148 1 CO₂Me 2-CN-Phenyl 149 2 CO₂Me 2-CN-Phenyl 150 3 CO₂Me 2-CN-Phenyl 151 1 CO₂tBu 2-CN-Phenyl 152 2 CO₂tBu 2-CN-Phenyl 153 3 CO₂tBu 2-CN-Phenyl 154 1 CONHMe 2-CN-Phenyl 155 2 CONHMe 2-CN-Phenyl 156 3 CONHMe 2-CN-Phenyl 157 1 SO₂Me 2-CN-Phenyl 158 2 SO₂Me 2-CN-Phenyl 159 3 SO₂Me 2-CN-Phenyl 160 1 SO₂NH₂ 2-CN-Phenyl 161 2 SO₂NH₂ 2-CN-Phenyl 162 3 SO₂NH₂ 2-CN-Phenyl 163 1 H 3-Me-Phenyl 164 2 H 3-Me-Phenyl 165 3 H 3-Me-Phenyl 166 1 Me 3-Me-Phenyl 167 2 Me 3-Me-Phenyl 168 3 Me 3-Me-Phenyl 169 1 CH₂Ph 3-Me-Phenyl 170 2 CH₂Ph 3-Me-Phenyl 171 3 CH₂Ph 3-Me-Phenyl 172 1 COMe 3-Me-Phenyl 173 2 COMe 3-Me-Phenyl 174 3 COMe 3-Me-Phenyl 175 1 CO₂Me 3-Me-Phenyl 176 2 CO₂Me 3-Me-Phenyl 177 3 CO₂Me 3-Me-Phenyl 178 1 CO₂tBu 3-Me-Phenyl 179 2 CO₂tBu 3-Me-Phenyl 180 3 CO₂tBu 3-Me-Phenyl 181 1 CONHMe 3-Me-Phenyl 182 2 CONHMe 3-Me-Phenyl 183 3 CONHMe 3-Me-Phenyl 184 1 SO₂Me 3-Me-Phenyl 185 2 SO₂Me 3-Me-Phenyl 186 3 SO₂Me 3-Me-Phenyl 187 1 SO₂NH₂ 3-Me-Phenyl 188 2 SO₂NH₂ 3-Me-Phenyl 189 3 SO₂NH₂ 3-Me-Phenyl 190 1 H 2-F-Phenyl 191 2 H 2-F-Phenyl 192 3 H 2-F-Phenyl 193 1 Me 2-F-Phenyl 194 2 Me 2-F-Phenyl 195 3 Me 2-F-Phenyl 196 1 CH₂Ph 2-F-Phenyl 197 2 CH₂Ph 2-F-Phenyl 198 3 CH₂Ph 2-F-Phenyl 199 1 COMe 2-F-Phenyl 200 2 COMe 2-F-Phenyl 201 3 COMe 2-F-Phenyl 202 1 CO₂Me 2-F-Phenyl 203 2 CO₂Me 2-F-Phenyl 204 3 CO₂Me 2-F-Phenyl 205 1 CO₂tBu 2-F-Phenyl 206 2 CO₂tBu 2-F-Phenyl 207 3 CO₂tBu 2-F-Phenyl 208 1 CONHMe 2-F-Phenyl 209 2 CONHMe 2-F-Phenyl 210 3 CONHMe 2-F-Phenyl 211 1 SO₂Me 2-F-Phenyl 212 2 SO₂Me 2-F-Phenyl 213 3 SO₂Me 2-F-Phenyl 214 1 SO₂NH₂ 2-F-Phenyl 215 2 SO₂NH₂ 2-F-Phenyl 216 3 SO₂NH₂ 2-F-Phenyl 217 1 H 4-F-Phenyl 218 2 H 4-F-Phenyl 219 3 H 4-F-Phenyl 220 1 Me 4-F-Phenyl 221 2 Me 4-F-Phenyl 222 3 Me 4-F-Phenyl 223 1 CH₂Ph 4-F-Phenyl 224 2 CH₂Ph 4-F-Phenyl 225 3 CH₂Ph 4-F-Phenyl 226 1 COMe 4-F-Phenyl 227 2 COMe 4-F-Phenyl 228 3 COMe 4-F-Phenyl 229 1 CO₂Me 4-F-Phenyl 230 2 CO₂Me 4-F-Phenyl 231 3 CO₂Me 4-F-Phenyl 232 1 CO₂tBu 4-F-Phenyl 233 2 CO₂tBu 4-F-Phenyl 234 3 CO₂tBu 4-F-Phenyl 235 1 CONHMe 4-F-Phenyl 236 2 CONHMe 4-F-Phenyl 237 3 CONHMe 4-F-Phenyl 238 1 SO₂Me 4-F-Phenyl 239 2 SO₂Me 4-F-Phenyl 240 3 SO₂Me 4-F-Phenyl 241 1 SO₂NH₂ 4-F-Phenyl 242 2 SO₂NH₂ 4-F-Phenyl 243 3 SO₂NH₂ 4-F-Phenyl 244 1 H 3-Cl-Phenyl 245 2 H 3-Cl-Phenyl 246 3 H 3-Cl-Phenyl 247 1 Me 3-Cl-Phenyl 248 2 Me 3-Cl-Phenyl 249 3 Me 3-Cl-Phenyl 250 1 CH₂Ph 3-Cl-Phenyl 251 2 CH₂Ph 3-Cl-Phenyl 252 3 CH₂Ph 3-Cl-Phenyl 253 1 COMe 3-Cl-Phenyl 254 2 COMe 3-Cl-Phenyl 255 3 COMe 3-Cl-Phenyl 256 1 CO₂Me 3-Cl-Phenyl 257 2 CO₂Me 3-Cl-Phenyl 258 3 CO₂Me 3-Cl-Phenyl 259 1 CO₂tBu 3-Cl-Phenyl 260 2 CO₂tBu 3-Cl-Phenyl 261 3 CO₂tBu 3-Cl-Phenyl 262 1 CONHMe 3-Cl-Phenyl 263 2 CONHMe 3-Cl-Phenyl 264 3 CONHMe 3-Cl-Phenyl 265 1 SO₂Me 3-Cl-Phenyl 266 2 SO₂Me 3-Cl-Phenyl 267 3 SO₂Me 3-Cl-Phenyl 268 1 SO₂NH₂ 3-Cl-Phenyl 269 2 SO₂NH₂ 3-Cl-Phenyl 270 3 SO₂NH₂ 3-Cl-Phenyl 271 1 H 2-Br-Phenyl 272 2 H 2-Br-Phenyl 273 3 H 2-Br-Phenyl 274 1 Me 2-Br-Phenyl 275 2 Me 2-Br-Phenyl 276 3 Me 2-Br-Phenyl 277 1 CH₂Ph 2-Br-Phenyl 278 2 CH₂Ph 2-Br-Phenyl 279 3 CH₂Ph 2-Br-Phenyl 280 1 COMe 2-Br-Phenyl 281 2 COMe 2-Br-Phenyl 282 3 COMe 2-Br-Phenyl 283 1 CO₂Me 2-Br-Phenyl 284 2 CO₂Me 2-Br-Phenyl 285 3 CO₂Me 2-Br-Phenyl 286 1 CO₂tBu 2-Br-Phenyl 287 2 CO₂tBu 2-Br-Phenyl 288 3 CO₂tBu 2-Br-Phenyl 289 1 CONHMe 2-Br-Phenyl 290 2 CONHMe 2-Br-Phenyl 291 3 CONHMe 2-Br-Phenyl 292 1 SO₂Me 2-Br-Phenyl 293 2 SO₂Me 2-Br-Phenyl 294 3 SO₂Me 2-Br-Phenyl 295 1 SO₂NH₂ 2-Br-Phenyl 296 2 SO₂NH₂ 2-Br-Phenyl 297 3 SO₂NH₂ 2-Br-Phenyl 298 1 H 4-Br-Phenyl 299 2 H 4-Br-Phenyl 300 3 H 4-Br-Phenyl 301 1 Me 4-Br-Phenyl 302 2 Me 4-Br-Phenyl 303 3 Me 4-Br-Phenyl 304 1 CH₂Ph 4-Br-Phenyl 305 2 CH₂Ph 4-Br-Phenyl 306 3 CH₂Ph 4-Br-Phenyl 307 1 COMe 4-Br-Phenyl 308 2 COMe 4-Br-Phenyl 309 3 COMe 4-Br-Phenyl 310 1 CO₂Me 4-Br-Phenyl 311 2 CO₂Me 4-Br-Phenyl 312 3 CO₂Me 4-Br-Phenyl 313 1 CO₂tBu 4-Br-Phenyl 314 2 CO₂tBu 4-Br-Phenyl 315 3 CO₂tBu 4-Br-Phenyl 316 1 CONHMe 4-Br-Phenyl 317 2 CONHMe 4-Br-Phenyl 318 3 CONHMe 4-Br-Phenyl 319 1 SO₂Me 4-Br-Phenyl 320 2 SO₂Me 4-Br-Phenyl 321 3 SO₂Me 4-Br-Phenyl 322 1 SO₂NH₂ 4-Br-Phenyl 323 2 SO₂NH₂ 4-Br-Phenyl 324 3 SO₂NH₂ 4-Br-Phenyl 325 1 H 3-CF₃-Phenyl 326 2 H 3-CF₃-Phenyl 327 3 H 3-CF₃-Phenyl 328 1 Me 3-CF₃-Phenyl 329 2 Me 3-CF₃-Phenyl 330 3 Me 3-CF₃-Phenyl 331 1 CH₂Ph 3-CF₃-Phenyl 332 2 CH₂Ph 3-CF₃-Phenyl 333 3 CH₂Ph 3-CF₃-Phenyl 334 1 COMe 3-CF₃-Phenyl 335 2 COMe 3-CF₃-Phenyl 336 3 COMe 3-CF₃-Phenyl 337 1 CO₂Me 3-CF₃-Phenyl 338 2 CO₂Me 3-CF₃-Phenyl 339 3 CO₂Me 3-CF₃-Phenyl 340 1 CO₂tBu 3-CF₃-Phenyl 341 2 CO₂tBu 3-CF₃-Phenyl 342 3 CO₂tBu 3-CF₃-Phenyl 343 1 CONHMe 3-CF₃-Phenyl 344 2 CONHMe 3-CF₃-Phenyl 345 3 CONHMe 3-CF₃-Phenyl 346 1 SO₂Me 3-CF₃-Phenyl 347 2 SO₂Me 3-CF₃-Phenyl 348 3 SO₂Me 3-CF₃-Phenyl 349 1 SO₂NH₂ 3-CF₃-Phenyl 350 2 SO₂NH₂ 3-CF₃-Phenyl 351 3 SO₂NH₂ 3-CF₃-Phenyl 352 1 H 2-iPr-Phenyl 353 2 H 2-iPr-Phenyl 354 3 H 2-iPr-Phenyl 355 1 Me 2-iPr-Phenyl 356 2 Me 2-iPr-Phenyl 357 3 Me 2-iPr-Phenyl 358 1 CH₂Ph 2-iPr-Phenyl 359 2 CH₂Ph 2-iPr-Phenyl 360 3 CH₂Ph 2-iPr-Phenyl 361 1 COMe 2-iPr-Phenyl 362 2 COMe 2-iPr-Phenyl 363 3 COMe 2-iPr-Phenyl 364 1 CO₂Me 2-iPr-Phenyl 365 2 CO₂Me 2-iPr-Phenyl 366 3 CO₂Me 2-iPr-Phenyl 367 1 CO₂tBu 2-iPr-Phenyl 368 2 CO₂tBu 2-iPr-Phenyl 369 3 CO₂tBu 2-iPr-Phenyl 370 1 CONHMe 2-iPr-Phenyl 371 2 CONHMe 2-iPr-Phenyl 372 3 CONHMe 2-iPr-Phenyl 373 1 SO₂Me 2-iPr-Phenyl 374 2 SO₂Me 2-iPr-Phenyl 375 3 SO₂Me 2-iPr-Phenyl 376 1 SO₂NH₂ 2-iPr-Phenyl 377 2 SO₂NH₂ 2-iPr-Phenyl 378 3 SO₂NH₂ 2-iPr-Phenyl 379 1 H 4-iPr-Phenyl 380 2 H 4-iPr-Phenyl 381 3 H 4-iPr-Phenyl 382 1 Me 4-iPr-Phenyl 383 2 Me 4-iPr-Phenyl 384 3 Me 4-iPr-Phenyl 385 1 CH₂Ph 4-iPr-Phenyl 386 2 CH₂Ph 4-iPr-Phenyl 387 3 CH₂Ph 4-iPr-Phenyl 388 1 COMe 4-iPr-Phenyl 389 2 COMe 4-iPr-Phenyl 390 3 COMe 4-iPr-Phenyl 391 1 CO₂Me 4-iPr-Phenyl 392 2 CO₂Me 4-iPr-Phenyl 393 3 CO₂Me 4-iPr-Phenyl 394 1 CO₂tBu 4-iPr-Phenyl 395 2 CO₂tBu 4-iPr-Phenyl 396 3 CO₂tBu 4-iPr-Phenyl 397 1 CONHMe 4-iPr-Phenyl 398 2 CONHMe 4-iPr-Phenyl 399 3 CONHMe 4-iPr-Phenyl 400 1 SO₂Me 4-iPr-Phenyl 401 2 SO₂Me 4-iPr-Phenyl 402 3 SO₂Me 4-iPr-Phenyl 403 1 SO₂NH₂ 4-iPr-Phenyl 404 2 SO₂NH₂ 4-iPr-Phenyl 405 3 SO₂NH₂ 4-iPr-Phenyl 406 1 H 3-NH₂-Phenyl 407 2 H 3-NH₂-Phenyl 408 3 H 3-NH₂-Phenyl 409 1 Me 3-NH₂-Phenyl 410 2 Me 3-NH₂-Phenyl 411 3 Me 3-NH₂-Phenyl 412 1 CH₂Ph 3-NH₂-Phenyl 413 2 CH₂Ph 3-NH₂-Phenyl 414 3 CH₂Ph 3-NH₂-Phenyl 415 1 COMe 3-NH₂-Phenyl 416 2 COMe 3-NH₂-Phenyl 417 3 COMe 3-NH₂-Phenyl 418 1 CO₂Me 3-NH₂-Phenyl 419 2 CO₂Me 3-NH₂-Phenyl 420 3 CO₂Me 3-NH₂-Phenyl 421 1 CO₂tBu 3-NH₂-Phenyl 422 2 CO₂tBu 3-NH₂-Phenyl 423 3 CO₂tBu 3-NH₂-Phenyl 424 1 CONHMe 3-NH₂-Phenyl 425 2 CONHMe 3-NH₂-Phenyl 426 3 CONHMe 3-NH₂-Phenyl 427 1 SO₂Me 3-NH₂-Phenyl 428 2 SO₂Me 3-NH₂-Phenyl 429 3 SO₂Me 3-NH₂-Phenyl 430 1 SO₂NH₂ 3-NH₂-Phenyl 431 2 SO₂NH₂ 3-NH₂-Phenyl 432 3 SO₂NH₂ 3-NH₂-Phenyl 433 1 H 2,4-di-Me-Phenyl 434 2 H 2,4-di-Me-Phenyl 435 3 H 2,4-di-Me-Phenyl 436 1 Me 2,4-di-Me-Phenyl 437 2 Me 2,4-di-Me-Phenyl 438 3 Me 2,4-di-Me-Phenyl 439 1 CH₂Ph 2,4-di-Me-Phenyl 440 2 CH₂Ph 2,4-di-Me-Phenyl 441 3 CH₂Ph 2,4-di-Me-Phenyl 442 1 COMe 2,4-di-Me-Phenyl 443 2 COMe 2,4-di-Me-Phenyl 444 3 COMe 2,4-di-Me-Phenyl 445 1 CO₂Me 2,4-di-Me-Phenyl 446 2 CO₂Me 2,4-di-Me-Phenyl 447 3 CO₂Me 2,4-di-Me-Phenyl 448 1 CO₂tBu 2,4-di-Me-Phenyl 449 2 CO₂tBu 2,4-di-Me-Phenyl 450 3 CO₂tBu 2,4-di-Me-Phenyl 451 1 CONHMe 2,4-di-Me-Phenyl 452 2 CONHMe 2,4-di-Me-Phenyl 453 3 CONHMe 2,4-di-Me-Phenyl 454 1 SO₂Me 2,4-di-Me-Phenyl 455 2 SO₂Me 2,4-di-Me-Phenyl 456 3 SO₂Me 2,4-di-Me-Phenyl 457 1 SO₂NH₂ 2,4-di-Me-Phenyl 458 2 SO₂NH₂ 2,4-di-Me-Phenyl 459 3 SO₂NH₂ 2,4-di-Me-Phenyl 460 1 H 2,6-di-iPr-Phenyl 461 2 H 2,6-di-iPr-Phenyl 462 3 H 2,6-di-iPr-Phenyl 463 1 Me 2,6-di-iPr-Phenyl 464 2 Me 2,6-di-iPr-Phenyl 465 3 Me 2,6-di-iPr-Phenyl 466 1 CH₂Ph 2,6-di-iPr-Phenyl 467 2 CH₂Ph 2,6-di-iPr-Phenyl 468 3 CH₂Ph 2,6-di-iPr-Phenyl 469 1 COMe 2,6-di-iPr-Phenyl 470 2 COMe 2,6-di-iPr-Phenyl 471 3 COMe 2,6-di-iPr-Phenyl 472 1 CO₂Me 2,6-di-iPr-Phenyl 473 2 CO₂Me 2,6-di-iPr-Phenyl 474 3 CO₂Me 2,6-di-iPr-Phenyl 475 1 CO₂tBu 2,6-di-iPr-Phenyl 476 2 CO₂tBu 2,6-di-iPr-Phenyl 477 3 CO₂tBu 2,6-di-iPr-Phenyl 478 1 CONHMe 2,6-di-iPr-Phenyl 479 2 CONHMe 2,6-di-iPr-Phenyl 480 3 CONHMe 2,6-di-iPr-Phenyl 481 1 SO₂Me 2,6-di-iPr-Phenyl 482 2 SO₂Me 2,6-di-iPr-Phenyl 483 3 SO₂Me 2,6-di-iPr-Phenyl 484 1 SO₂NH₂ 2,6-di-iPr-Phenyl 485 2 SO₂NH₂ 2,6-di-iPr-Phenyl 486 3 SO₂NH₂ 2,6-di-iPr-Phenyl 487 1 H 3-Ph-Phenyl 488 2 H 3-Ph-Phenyl 489 3 H 3-Ph-Phenyl 490 1 Me 3-Ph-Phenyl 491 2 Me 3-Ph-Phenyl 492 3 Me 3-Ph-Phenyl 493 1 CH₂Ph 3-Ph-Phenyl 494 2 CH₂Ph 3-Ph-Phenyl 495 3 CH₂Ph 3-Ph-Phenyl 496 1 COMe 3-Ph-Phenyl 497 2 COMe 3-Ph-Phenyl 498 3 COMe 3-Ph-Phenyl 499 1 CO₂Me 3-Ph-Phenyl 500 2 CO₂Me 3-Ph-Phenyl 501 3 CO₂Me 3-Ph-Phenyl 502 1 CO₂tBu 3-Ph-Phenyl 503 2 CO₂tBu 3-Ph-Phenyl 504 3 CO₂tBu 3-Ph-Phenyl 505 1 CONHMe 3-Ph-Phenyl 506 2 CONHMe 3-Ph-Phenyl 507 3 CONHMe 3-Ph-Phenyl 508 1 SO₂Me 3-Ph-Phenyl 509 2 SO₂Me 3-Ph-Phenyl 510 3 SO₂Me 3-Ph-Phenyl 511 1 SO₂NH₂ 3-Ph-Phenyl 512 2 SO₂NH₂ 3-Ph-Phenyl 513 3 SO₂NH₂ 3-Ph-Phenyl 514 1 H 2-morpholino-phenyl 515 2 H 2-morpholino-phenyl 516 3 H 2-morpholino-phenyl 517 1 Me 2-morpholino-phenyl 518 2 Me 2-morpholino-phenyl 519 3 Me 2-morpholino-phenyl 520 1 CH₂Ph 2-morpholino-phenyl 521 2 CH₂Ph 2-morpholino-phenyl 522 3 CH₂Ph 2-morpholino-phenyl 523 1 COMe 2-morpholino-phenyl 524 2 COMe 2-morpholino-phenyl 525 3 COMe 2-morpholino-phenyl 526 1 CO₂Me 2-morpholino-phenyl 527 2 CO₂Me 2-morpholino-phenyl 528 3 CO₂Me 2-morpholino-phenyl 529 1 CO₂tBu 2-morpholino-phenyl 530 2 CO₂tBu 2-morpholino-phenyl 531 3 CO₂tBu 2-morpholino-phenyl 532 1 CONHMe 2-morpholino-phenyl 533 2 CONHMe 2-morpholino-phenyl 534 3 CONHMe 2-morpholino-phenyl 535 1 SO₂Me 2-morpholino-phenyl 536 2 SO₂Me 2-morpholino-phenyl 537 3 SO₂Me 2-morpholino-phenyl 538 1 SO₂NH₂ 2-morpholino-phenyl 539 2 SO₂NH₂ 2-morpholino-phenyl 540 3 SO₂NH₂ 2-morpholino-phenyl 541 1 H 4-morpholino-phenyl 542 2 H 4-morpholino-phenyl 543 3 H 4-morpholino-phenyl 544 1 Me 4-morpholino-phenyl 545 2 Me 4-morpholino-phenyl 546 3 Me 4-morpholino-phenyl 547 1 CH₂Ph 4-morpholino-phenyl 548 2 CH₂Ph 4-morpholino-phenyl 549 3 CH₂Ph 4-morpholino-phenyl 550 1 COMe 4-morpholino-phenyl 551 2 COMe 4-morpholino-phenyl 552 3 COMe 4-morpholino-phenyl 553 1 CO₂Me 4-morpholino-phenyl 554 2 CO₂Me 4-morpholino-phenyl 555 3 CO₂Me 4-morpholino-phenyl 556 1 CO₂tBu 4-morpholino-phenyl 557 2 CO₂tBu 4-morpholino-phenyl 558 3 CO₂tBu 4-morpholino-phenyl 559 1 CONHMe 4-morpholino-phenyl 560 2 CONHMe 4-morpholino-phenyl 561 3 CONHMe 4-morpholino-phenyl 562 1 SO₂Me 4-morpholino-phenyl 563 2 SO₂Me 4-morpholino-phenyl 564 3 SO₂Me 4-morpholino-phenyl 565 1 SO₂NH₂ 4-morpholino-phenyl 566 2 SO₂NH₂ 4-morpholino-phenyl 567 3 SO₂NH₂ 4-morpholino-phenyl 568 1 H 2-pyrimidinyl 569 2 H 2-pyrimidinyl 570 3 H 2-pyrimidinyl 571 1 Me 2-pyrimidinyl 572 2 Me 2-pyrimidinyl 573 3 Me 2-pyrimidinyl 574 1 CH₂Ph 2-pyrimidinyl 575 2 CH₂Ph 2-pyrimidinyl 576 3 CH₂Ph 2-pyrimidinyl 577 1 COMe 2-pyrimidinyl 578 2 COMe 2-pyrimidinyl 579 3 COMe 2-pyrimidinyl 580 1 CO₂Me 2-pyrimidinyl 581 2 CO₂Me 2-pyrimidinyl 582 3 CO₂Me 2-pyrimidinyl 583 1 CO₂tBu 2-pyrimidinyl 584 2 CO₂tBu 2-pyrimidinyl 585 3 CO₂tBu 2-pyrimidinyl 586 1 CONHMe 2-pyrimidinyl 587 2 CONHMe 2-pyrimidinyl 588 3 CONHMe 2-pyrimidinyl 589 1 SO₂Me 2-pyrimidinyl 590 2 SO₂Me 2-pyrimidinyl 591 3 SO₂Me 2-pyrimidinyl 592 1 SO₂NH₂ 2-pyrimidinyl 593 2 SO₂NH₂ 2-pyrimidinyl 594 3 SO₂NH₂ 2-pyrimidinyl 595 1 H 2-methyl-1H- benzo[d]imidazol-4-yl 596 2 H 2-methyl-1H- benzo[d]imidazol-4-yl 597 3 H 2-methyl-1H- benzo[d]imidazol-4-yl 598 1 Me 2-methyl-1H- benzo[d]imidazol-4-yl 599 2 Me 2-methyl-1H- benzo[d]imidazol-4-yl 600 3 Me 2-methyl-1H- benzo[d]imidazol-4-yl 601 1 CH₂Ph 2-methyl-1H- benzo[d]imidazol-4-yl 602 2 CH₂Ph 2-methyl-1H- benzo[d]imidazol-4-yl 603 3 CH₂Ph 2-methyl-1H- benzo[d]imidazol-4-yl 604 1 COMe 2-methyl-1H- benzo[d]imidazol-4-yl 605 2 COMe 2-methyl-1H- benzo[d]imidazol-4-yl 606 3 COMe 2-methyl-1H- benzo[d]imidazol-4-yl 607 1 CO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 608 2 CO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 609 3 CO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 610 1 CO₂tBu 2-methyl-1H- benzo[d]imidazol-4-yl 611 2 CO₂tBu 2-methyl-1H- benzo[d]imidazol-4-yl 612 3 CO₂tBu 2-methyl-1H- benzo[d]imidazol-4-yl 613 1 CONHMe 2-methyl-1H- benzo[d]imidazol-4-yl 614 2 CONHMe 2-methyl-1H- benzo[d]imidazol-4-yl 615 3 CONHMe 2-methyl-1H- benzo[d]imidazol-4-yl 616 1 SO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 617 2 SO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 618 3 SO₂Me 2-methyl-1H- benzo[d]imidazol-4-yl 619 1 SO₂NH₂ 2-methyl-1H- benzo[d]imidazol-4-yl 620 2 SO₂NH₂ 2-methyl-1H- benzo[d]imidazol-4-yl 621 3 SO₂NH₂ 2-methyl-1H- benzo[d]imidazol-4-yl 622 1 H 4-OH-Phenyl 623 2 H 4-OH-Phenyl 624 3 H 4-OH-Phenyl 625 1 Me 4-OH-Phenyl 626 2 Me 4-OH-Phenyl 627 3 Me 4-OH-Phenyl 628 1 CH₂Ph 4-OH-Phenyl 629 2 CH₂Ph 4-OH-Phenyl 630 3 CH₂Ph 4-OH-Phenyl 631 1 COMe 4-OH-Phenyl 632 2 COMe 4-OH-Phenyl 633 3 COMe 4-OH-Phenyl 634 1 CO₂Me 4-OH-Phenyl 635 2 CO₂Me 4-OH-Phenyl 636 3 CO₂Me 4-OH-Phenyl 637 1 CO₂tBu 4-OH-Phenyl 638 2 CO₂tBu 4-OH-Phenyl 639 3 CO₂tBu 4-OH-Phenyl 640 1 CONHMe 4-OH-Phenyl 641 2 CONHMe 4-OH-Phenyl 642 3 CONHMe 4-OH-Phenyl 643 1 SO₂Me 4-OH-Phenyl 644 2 SO₂Me 4-OH-Phenyl 645 3 SO₂Me 4-OH-Phenyl 646 1 SO₂NH₂ 4-OH-Phenyl 647 2 SO₂NH₂ 4-OH-Phenyl 648 3 SO₂NH₂ 4-OH-Phenyl 649 1 H 2-OH-Phenyl 650 2 H 2-OH-Phenyl 651 3 H 2-OH-Phenyl 652 1 Me 2-OH-Phenyl 653 2 Me 2-OH-Phenyl 654 3 Me 2-OH-Phenyl 655 1 CH₂Ph 2-OH-Phenyl 656 2 CH₂Ph 2-OH-Phenyl 657 3 CH₂Ph 2-OH-Phenyl 658 1 COMe 2-OH-Phenyl 659 2 COMe 2-OH-Phenyl 660 3 COMe 2-OH-Phenyl 661 1 CO₂Me 2-OH-Phenyl 662 2 CO₂Me 2-OH-Phenyl 663 3 CO₂Me 2-OH-Phenyl 664 1 CO₂tBu 2-OH-Phenyl 665 2 CO₂tBu 2-OH-Phenyl 666 3 CO₂tBu 2-OH-Phenyl 667 1 CONHMe 2-OH-Phenyl 668 2 CONHMe 2-OH-Phenyl 669 3 CONHMe 2-OH-Phenyl 670 1 SO₂Me 2-OH-Phenyl 671 2 SO₂Me 2-OH-Phenyl 672 3 SO₂Me 2-OH-Phenyl 673 1 SO₂NH₂ 2-OH-Phenyl 674 2 SO₂NH₂ 2-OH-Phenyl 675 3 SO₂NH₂ 2-OH-Phenyl 676 1 H 4-OMe-Phenyl 677 2 H 4-OMe-Phenyl 678 3 H 4-OMe-Phenyl 679 1 Me 4-OMe-Phenyl 680 2 Me 4-OMe-Phenyl 681 3 Me 4-OMe-Phenyl 682 1 CH₂Ph 4-OMe-Phenyl 683 2 CH₂Ph 4-OMe-Phenyl 684 3 CH₂Ph 4-OMe-Phenyl 685 1 COMe 4-OMe-Phenyl 686 2 COMe 4-OMe-Phenyl 687 3 COMe 4-OMe-Phenyl 688 1 CO₂Me 4-OMe-Phenyl 689 2 CO₂Me 4-OMe-Phenyl 690 3 CO₂Me 4-OMe-Phenyl 691 1 CO₂tBu 4-OMe-Phenyl 692 2 CO₂tBu 4-OMe-Phenyl 693 3 CO₂tBu 4-OMe-Phenyl 694 1 CONHMe 4-OMe-Phenyl 695 2 CONHMe 4-OMe-Phenyl 696 3 CONHMe 4-OMe-Phenyl 697 1 SO₂Me 4-OMe-Phenyl 698 2 SO₂Me 4-OMe-Phenyl 699 3 SO₂Me 4-OMe-Phenyl 700 1 SO₂NH₂ 4-OMe-Phenyl 701 2 SO₂NH₂ 4-OMe-Phenyl 702 3 SO₂NH₂ 4-OMe-Phenyl 703 1 H 2-OMe-Phenyl 704 2 H 2-OMe-Phenyl 705 3 H 2-OMe-Phenyl 706 1 Me 2-OMe-Phenyl 707 2 Me 2-OMe-Phenyl 708 3 Me 2-OMe-Phenyl 709 1 CH₂Ph 2-OMe-Phenyl 710 2 CH₂Ph 2-OMe-Phenyl 711 3 CH₂Ph 2-OMe-Phenyl 712 1 COMe 2-OMe-Phenyl 713 2 COMe 2-OMe-Phenyl 714 3 COMe 2-OMe-Phenyl 715 1 CO₂Me 2-OMe-Phenyl 716 2 CO₂Me 2-OMe-Phenyl 717 3 CO₂Me 2-OMe-Phenyl 718 1 CO₂tBu 2-OMe-Phenyl 719 2 CO₂tBu 2-OMe-Phenyl 720 3 CO₂tBu 2-OMe-Phenyl 721 1 CONHMe 2-OMe-Phenyl 722 2 CONHMe 2-OMe-Phenyl 723 3 CONHMe 2-OMe-Phenyl 724 1 SO₂Me 2-OMe-Phenyl 725 2 SO₂Me 2-OMe-Phenyl 726 3 SO₂Me 2-OMe-Phenyl 727 1 SO₂NH₂ 2-OMe-Phenyl 728 2 SO₂NH₂ 2-OMe-Phenyl 729 3 SO₂NH₂ 2-OMe-Phenyl 730 1 H 3-CN-Phenyl 731 2 H 3-CN-Phenyl 732 3 H 3-CN-Phenyl 733 1 Me 3-CN-Phenyl 734 2 Me 3-CN-Phenyl 735 3 Me 3-CN-Phenyl 736 1 CH₂Ph 3-CN-Phenyl 737 2 CH₂Ph 3-CN-Phenyl 738 3 CH₂Ph 3-CN-Phenyl 739 1 COMe 3-CN-Phenyl 740 2 COMe 3-CN-Phenyl 741 3 COMe 3-CN-Phenyl 742 1 CO₂Me 3-CN-Phenyl 743 2 CO₂Me 3-CN-Phenyl 744 3 CO₂Me 3-CN-Phenyl 745 1 CO₂tBu 3-CN-Phenyl 746 2 CO₂tBu 3-CN-Phenyl 747 3 CO₂tBu 3-CN-Phenyl 748 1 CONHMe 3-CN-Phenyl 749 2 CONHMe 3-CN-Phenyl 750 3 CONHMe 3-CN-Phenyl 751 1 SO₂Me 3-CN-Phenyl 752 2 SO₂Me 3-CN-Phenyl 753 3 SO₂Me 3-CN-Phenyl 754 1 SO₂NH₂ 3-CN-Phenyl 755 2 SO₂NH₂ 3-CN-Phenyl 756 3 SO₂NH₂ 3-CN-Phenyl 757 1 H 2-Me-Phenyl 758 2 H 2-Me-Phenyl 759 3 H 2-Me-Phenyl 760 1 Me 2-Me-Phenyl 761 2 Me 2-Me-Phenyl 762 3 Me 2-Me-Phenyl 763 1 CH₂Ph 2-Me-Phenyl 764 2 CH₂Ph 2-Me-Phenyl 765 3 CH₂Ph 2-Me-Phenyl 766 1 COMe 2-Me-Phenyl 767 2 COMe 2-Me-Phenyl 768 3 COMe 2-Me-Phenyl 769 1 CO₂Me 2-Me-Phenyl 770 2 CO₂Me 2-Me-Phenyl 771 3 CO₂Me 2-Me-Phenyl 772 1 CO₂tBu 2-Me-Phenyl 773 2 CO₂tBu 2-Me-Phenyl 774 3 CO₂tBu 2-Me-Phenyl 775 1 CONHMe 2-Me-Phenyl 776 2 CONHMe 2-Me-Phenyl 777 3 CONHMe 2-Me-Phenyl 778 1 SO₂Me 2-Me-Phenyl 779 2 SO₂Me 2-Me-Phenyl 780 3 SO₂Me 2-Me-Phenyl 781 1 SO₂NH₂ 2-Me-Phenyl 782 2 SO₂NH₂ 2-Me-Phenyl 783 3 SO₂NH₂ 2-Me-Phenyl 784 1 H 4-Me-Phenyl 785 2 H 4-Me-Phenyl 786 3 H 4-Me-Phenyl 787 1 Me 4-Me-Phenyl 788 2 Me 4-Me-Phenyl 789 3 Me 4-Me-Phenyl 790 1 CH₂Ph 4-Me-Phenyl 791 2 CH₂Ph 4-Me-Phenyl 792 3 CH₂Ph 4-Me-Phenyl 793 1 COMe 4-Me-Phenyl 794 2 COMe 4-Me-Phenyl 795 3 COMe 4-Me-Phenyl 796 1 CO₂Me 4-Me-Phenyl 797 2 CO₂Me 4-Me-Phenyl 798 3 CO₂Me 4-Me-Phenyl 799 1 CO₂tBu 4-Me-Phenyl 800 2 CO₂tBu 4-Me-Phenyl 801 3 CO₂tBu 4-Me-Phenyl 802 1 CONHMe 4-Me-Phenyl 803 2 CONHMe 4-Me-Phenyl 804 3 CONHMe 4-Me-Phenyl 805 1 SO₂Me 4-Me-Phenyl 806 2 SO₂Me 4-Me-Phenyl 807 3 SO₂Me 4-Me-Phenyl 808 1 SO₂NH₂ 4-Me-Phenyl 809 2 SO₂NH₂ 4-Me-Phenyl 810 3 SO₂NH₂ 4-Me-Phenyl 811 1 H 3-F-Phenyl 812 2 H 3-F-Phenyl 813 3 H 3-F-Phenyl 814 1 Me 3-F-Phenyl 815 2 Me 3-F-Phenyl 816 3 Me 3-F-Phenyl 817 1 CH₂Ph 3-F-Phenyl 818 2 CH₂Ph 3-F-Phenyl 819 3 CH₂Ph 3-F-Phenyl 820 1 COMe 3-F-Phenyl 821 2 COMe 3-F-Phenyl 822 3 COMe 3-F-Phenyl 823 1 CO₂Me 3-F-Phenyl 824 2 CO₂Me 3-F-Phenyl 825 3 CO₂Me 3-F-Phenyl 826 1 CO₂tBu 3-F-Phenyl 827 2 CO₂tBu 3-F-Phenyl 828 3 CO₂tBu 3-F-Phenyl 829 1 CONHMe 3-F-Phenyl 830 2 CONHMe 3-F-Phenyl 831 3 CONHMe 3-F-Phenyl 832 1 SO₂Me 3-F-Phenyl 833 2 SO₂Me 3-F-Phenyl 834 3 SO₂Me 3-F-Phenyl 835 1 SO₂NH₂ 3-F-Phenyl 836 2 SO₂NH₂ 3-F-Phenyl 837 3 SO₂NH₂ 3-F-Phenyl 838 1 H 2-Cl-Phenyl 839 2 H 2-Cl-Phenyl 840 3 H 2-Cl-Phenyl 841 1 Me 2-Cl-Phenyl 842 2 Me 2-Cl-Phenyl 843 3 Me 2-Cl-Phenyl 844 1 CH₂Ph 2-Cl-Phenyl 845 2 CH₂Ph 2-Cl-Phenyl 846 3 CH₂Ph 2-Cl-Phenyl 847 1 COMe 2-Cl-Phenyl 848 2 COMe 2-Cl-Phenyl 849 3 COMe 2-Cl-Phenyl 850 1 CO₂Me 2-Cl-Phenyl 851 2 CO₂Me 2-Cl-Phenyl 852 3 CO₂Me 2-Cl-Phenyl 853 1 CO₂tBu 2-Cl-Phenyl 854 2 CO₂tBu 2-Cl-Phenyl 855 3 CO₂tBu 2-Cl-Phenyl 856 1 CONHMe 2-Cl-Phenyl 857 2 CONHMe 2-Cl-Phenyl 858 3 CONHMe 2-Cl-Phenyl 859 1 SO₂Me 2-Cl-Phenyl 860 2 SO₂Me 2-Cl-Phenyl 861 3 SO₂Me 2-Cl-Phenyl 862 1 SO₂NH₂ 2-Cl-Phenyl 863 2 SO₂NH₂ 2-Cl-Phenyl 864 3 SO₂NH₂ 2-Cl-Phenyl 865 1 H 4-Cl-Phenyl 866 2 H 4-Cl-Phenyl 867 3 H 4-Cl-Phenyl 868 1 Me 4-Cl-Phenyl 869 2 Me 4-Cl-Phenyl 870 3 Me 4-Cl-Phenyl 871 1 CH₂Ph 4-Cl-Phenyl 872 2 CH₂Ph 4-Cl-Phenyl 873 3 CH₂Ph 4-Cl-Phenyl 874 1 COMe 4-Cl-Phenyl 875 2 COMe 4-Cl-Phenyl 876 3 COMe 4-Cl-Phenyl 877 1 CO₂Me 4-Cl-Phenyl 878 2 CO₂Me 4-Cl-Phenyl 879 3 CO₂Me 4-Cl-Phenyl 880 1 CO₂tBu 4-Cl-Phenyl 881 2 CO₂tBu 4-Cl-Phenyl 882 3 CO₂tBu 4-Cl-Phenyl 883 1 CONHMe 4-Cl-Phenyl 884 2 CONHMe 4-Cl-Phenyl 885 3 CONHMe 4-Cl-Phenyl 886 1 SO₂Me 4-Cl-Phenyl 887 2 SO₂Me 4-Cl-Phenyl 888 3 SO₂Me 4-Cl-Phenyl 889 1 SO₂NH₂ 4-Cl-Phenyl 890 2 SO₂NH₂ 4-Cl-Phenyl 891 3 SO₂NH₂ 4-Cl-Phenyl 892 1 H 3-Br-Phenyl 893 2 H 3-Br-Phenyl 894 3 H 3-Br-Phenyl 895 1 Me 3-Br-Phenyl 896 2 Me 3-Br-Phenyl 897 3 Me 3-Br-Phenyl 898 1 CH₂Ph 3-Br-Phenyl 899 2 CH₂Ph 3-Br-Phenyl 900 3 CH₂Ph 3-Br-Phenyl 901 1 COMe 3-Br-Phenyl 902 2 COMe 3-Br-Phenyl 903 3 COMe 3-Br-Phenyl 904 1 CO₂Me 3-Br-Phenyl 905 2 CO₂Me 3-Br-Phenyl 906 3 CO₂Me 3-Br-Phenyl 907 1 CO₂tBu 3-Br-Phenyl 908 2 CO₂tBu 3-Br-Phenyl 909 3 CO₂tBu 3-Br-Phenyl 910 1 CONHMe 3-Br-Phenyl 911 2 CONHMe 3-Br-Phenyl 912 3 CONHMe 3-Br-Phenyl 913 1 SO₂Me 3-Br-Phenyl 914 2 SO₂Me 3-Br-Phenyl 915 3 SO₂Me 3-Br-Phenyl 916 1 SO₂NH₂ 3-Br-Phenyl 917 2 SO₂NH₂ 3-Br-Phenyl 918 3 SO₂NH₂ 3-Br-Phenyl 919 1 H 2-CF₃-Phenyl 920 2 H 2-CF₃-Phenyl 921 3 H 2-CF₃-Phenyl 922 1 Me 2-CF₃-Phenyl 923 2 Me 2-CF₃-Phenyl 924 3 Me 2-CF₃-Phenyl 925 1 CH₂Ph 2-CF₃-Phenyl 926 2 CH₂Ph 2-CF₃-Phenyl 927 3 CH₂Ph 2-CF₃-Phenyl 928 1 COMe 2-CF₃-Phenyl 929 2 COMe 2-CF₃-Phenyl 930 3 COMe 2-CF₃-Phenyl 931 1 CO₂Me 2-CF₃-Phenyl 932 2 CO₂Me 2-CF₃-Phenyl 933 3 CO₂Me 2-CF₃-Phenyl 934 1 CO₂tBu 2-CF₃-Phenyl 935 2 CO₂tBu 2-CF₃-Phenyl 936 3 CO₂tBu 2-CF₃-Phenyl 937 1 CONHMe 2-CF₃-Phenyl 938 2 CONHMe 2-CF₃-Phenyl 939 3 CONHMe 2-CF₃-Phenyl 940 1 SO₂Me 2-CF₃-Phenyl 941 2 SO₂Me 2-CF₃-Phenyl 942 3 SO₂Me 2-CF₃-Phenyl 943 1 SO₂NH₂ 2-CF₃-Phenyl 944 2 SO₂NH₂ 2-CF₃-Phenyl 945 3 SO₂NH₂ 2-CF₃-Phenyl 946 1 H 4-CF₃-Phenyl 947 2 H 4-CF₃-Phenyl 948 3 H 4-CF₃-Phenyl 949 1 Me 4-CF₃-Phenyl 950 2 Me 4-CF₃-Phenyl 951 3 Me 4-CF₃-Phenyl 952 1 CH₂Ph 4-CF₃-Phenyl 953 2 CH₂Ph 4-CF₃-Phenyl 954 3 CH₂Ph 4-CF₃-Phenyl 955 1 COMe 4-CF₃-Phenyl 956 2 COMe 4-CF₃-Phenyl 957 3 COMe 4-CF₃-Phenyl 958 1 CO₂Me 4-CF₃-Phenyl 959 2 CO₂Me 4-CF₃-Phenyl 960 3 CO₂Me 4-CF₃-Phenyl 961 1 CO₂tBu 4-CF₃-Phenyl 962 2 CO₂tBu 4-CF₃-Phenyl 963 3 CO₂tBu 4-CF₃-Phenyl 964 1 CONHMe 4-CF₃-Phenyl 965 2 CONHMe 4-CF₃-Phenyl 966 3 CONHMe 4-CF₃-Phenyl 967 1 SO₂Me 4-CF₃-Phenyl 968 2 SO₂Me 4-CF₃-Phenyl 969 3 SO₂Me 4-CF₃-Phenyl 970 1 SO₂NH₂ 4-CF₃-Phenyl 971 2 SO₂NH₂ 4-CF₃-Phenyl 972 3 SO₂NH₂ 4-CF₃-Phenyl 973 1 H 3-iPr-Phenyl 974 2 H 3-iPr-Phenyl 975 3 H 3-iPr-Phenyl 976 1 Me 3-iPr-Phenyl 977 2 Me 3-iPr-Phenyl 978 3 Me 3-iPr-Phenyl 979 1 CH₂Ph 3-iPr-Phenyl 980 2 CH₂Ph 3-iPr-Phenyl 981 3 CH₂Ph 3-iPr-Phenyl 982 1 COMe 3-iPr-Phenyl 983 2 COMe 3-iPr-Phenyl 984 3 COMe 3-iPr-Phenyl 985 1 CO₂Me 3-iPr-Phenyl 986 2 CO₂Me 3-iPr-Phenyl 987 3 CO₂Me 3-iPr-Phenyl 988 1 CO₂tBu 3-iPr-Phenyl 989 2 CO₂tBu 3-iPr-Phenyl 990 3 CO₂tBu 3-iPr-Phenyl 991 1 CONHMe 3-iPr-Phenyl 992 2 CONHMe 3-iPr-Phenyl 993 3 CONHMe 3-iPr-Phenyl 994 1 SO₂Me 3-iPr-Phenyl 995 2 SO₂Me 3-iPr-Phenyl 996 3 SO₂Me 3-iPr-Phenyl 997 1 SO₂NH₂ 3-iPr-Phenyl 998 2 SO₂NH₂ 3-iPr-Phenyl 999 3 SO₂NH₂ 3-iPr-Phenyl 1000 1 H 4-NH₂-Phenyl 1001 2 H 4-NH₂-Phenyl 1002 3 H 4-NH₂-Phenyl 1003 1 Me 4-NH₂-Phenyl 1004 2 Me 4-NH₂-Phenyl 1005 3 Me 4-NH₂-Phenyl 1006 1 CH₂Ph 4-NH₂-Phenyl 1007 2 CH₂Ph 4-NH₂-Phenyl 1008 3 CH₂Ph 4-NH₂-Phenyl 1009 1 COMe 4-NH₂-Phenyl 1010 2 COMe 4-NH₂-Phenyl 1011 3 COMe 4-NH₂-Phenyl 1012 1 CO₂Me 4-NH₂-Phenyl 1013 2 CO₂Me 4-NH₂-Phenyl 1014 3 CO₂Me 4-NH₂-Phenyl 1015 1 CO₂tBu 4-NH₂-Phenyl 1016 2 CO₂tBu 4-NH₂-Phenyl 1017 3 CO₂tBu 4-NH₂-Phenyl 1018 1 CONHMe 4-NH₂-Phenyl 1019 2 CONHMe 4-NH₂-Phenyl 1020 3 CONHMe 4-NH₂-Phenyl 1021 1 SO₂Me 4-NH₂-Phenyl 1022 2 SO₂Me 4-NH₂-Phenyl 1023 3 SO₂Me 4-NH₂-Phenyl 1024 1 SO₂NH₂ 4-NH₂-Phenyl 1025 2 SO₂NH₂ 4-NH₂-Phenyl 1026 3 SO₂NH₂ 4-NH₂-Phenyl 1027 1 H 2-NH₂-Phenyl 1028 2 H 2-NH₂-Phenyl 1029 3 H 2-NH₂-Phenyl 1030 1 Me 2-NH₂-Phenyl 1031 2 Me 2-NH₂-Phenyl 1032 3 Me 2-NH₂-Phenyl 1033 1 CH₂Ph 2-NH₂-Phenyl 1034 2 CH₂Ph 2-NH₂-Phenyl 1035 3 CH₂Ph 2-NH₂-Phenyl 1036 1 COMe 2-NH₂-Phenyl 1037 2 COMe 2-NH₂-Phenyl 1038 3 COMe 2-NH₂-Phenyl 1039 1 CO₂Me 2-NH₂-Phenyl 1040 2 CO₂Me 2-NH₂-Phenyl 1041 3 CO₂Me 2-NH₂-Phenyl 1042 1 CO₂tBu 2-NH₂-Phenyl 1043 2 CO₂tBu 2-NH₂-Phenyl 1044 3 CO₂tBu 2-NH₂-Phenyl 1045 1 CONHMe 2-NH₂-Phenyl 1046 2 CONHMe 2-NH₂-Phenyl 1047 3 CONHMe 2-NH₂-Phenyl 1048 1 SO₂Me 2-NH₂-Phenyl 1049 2 SO₂Me 2-NH₂-Phenyl 1050 3 SO₂Me 2-NH₂-Phenyl 1051 1 SO₂NH₂ 2-NH₂-Phenyl 1052 2 SO₂NH₂ 2-NH₂-Phenyl 1053 3 SO₂NH₂ 2-NH₂-Phenyl 1054 1 H 2,6-di-Me-Phenyl 1055 2 H 2,6-di-Me-Phenyl 1056 3 H 2,6-di-Me-Phenyl 1057 1 Me 2,6-di-Me-Phenyl 1058 2 Me 2,6-di-Me-Phenyl 1059 3 Me 2,6-di-Me-Phenyl 1060 1 CH₂Ph 2,6-di-Me-Phenyl 1061 2 CH₂Ph 2,6-di-Me-Phenyl 1062 3 CH₂Ph 2,6-di-Me-Phenyl 1063 1 COMe 2,6-di-Me-Phenyl 1064 2 COMe 2,6-di-Me-Phenyl 1065 3 COMe 2,6-di-Me-Phenyl 1066 1 CO₂Me 2,6-di-Me-Phenyl 1067 2 CO₂Me 2,6-di-Me-Phenyl 1068 3 CO₂Me 2,6-di-Me-Phenyl 1069 1 CO₂tBu 2,6-di-Me-Phenyl 1070 2 CO₂tBu 2,6-di-Me-Phenyl 1071 3 CO₂tBu 2,6-di-Me-Phenyl 1072 1 CONHMe 2,6-di-Me-Phenyl 1073 2 CONHMe 2,6-di-Me-Phenyl 1074 3 CONHMe 2,6-di-Me-Phenyl 1075 1 SO₂Me 2,6-di-Me-Phenyl 1076 2 SO₂Me 2,6-di-Me-Phenyl 1077 3 SO₂Me 2,6-di-Me-Phenyl 1078 1 SO₂NH₂ 2,6-di-Me-Phenyl 1079 2 SO₂NH₂ 2,6-di-Me-Phenyl 1080 3 SO₂NH₂ 2,6-di-Me-Phenyl 1081 1 H 2-Ph-Phenyl 1082 2 H 2-Ph-Phenyl 1083 3 H 2-Ph-Phenyl 1084 1 Me 2-Ph-Phenyl 1085 2 Me 2-Ph-Phenyl 1086 3 Me 2-Ph-Phenyl 1087 1 CH₂Ph 2-Ph-Phenyl 1088 2 CH₂Ph 2-Ph-Phenyl 1089 3 CH₂Ph 2-Ph-Phenyl 1090 1 COMe 2-Ph-Phenyl 1091 2 COMe 2-Ph-Phenyl 1092 3 COMe 2-Ph-Phenyl 1093 1 CO₂Me 2-Ph-Phenyl 1094 2 CO₂Me 2-Ph-Phenyl 1095 3 CO₂Me 2-Ph-Phenyl 1096 1 CO₂tBu 2-Ph-Phenyl 1097 2 CO₂tBu 2-Ph-Phenyl 1098 3 CO₂tBu 2-Ph-Phenyl 1099 1 CONHMe 2-Ph-Phenyl 1100 2 CONHMe 2-Ph-Phenyl 1101 3 CONHMe 2-Ph-Phenyl 1102 1 SO₂Me 2-Ph-Phenyl 1103 2 SO₂Me 2-Ph-Phenyl 1104 3 SO₂Me 2-Ph-Phenyl 1105 1 SO₂NH₂ 2-Ph-Phenyl 1106 2 SO₂NH₂ 2-Ph-Phenyl 1107 3 SO₂NH₂ 2-Ph-Phenyl 1108 1 H 4-Ph-Phenyl 1109 2 H 4-Ph-Phenyl 1110 3 H 4-Ph-Phenyl 1111 1 Me 4-Ph-Phenyl 1112 2 Me 4-Ph-Phenyl 1113 3 Me 4-Ph-Phenyl 1114 1 CH₂Ph 4-Ph-Phenyl 1115 2 CH₂Ph 4-Ph-Phenyl 1116 3 CH₂Ph 4-Ph-Phenyl 1117 1 COMe 4-Ph-Phenyl 1118 2 COMe 4-Ph-Phenyl 1119 3 COMe 4-Ph-Phenyl 1120 1 CO₂Me 4-Ph-Phenyl 1121 2 CO₂Me 4-Ph-Phenyl 1122 3 CO₂Me 4-Ph-Phenyl 1123 1 CO₂tBu 4-Ph-Phenyl 1124 2 CO₂tBu 4-Ph-Phenyl 1125 3 CO₂tBu 4-Ph-Phenyl 1126 1 CONHMe 4-Ph-Phenyl 1127 2 CONHMe 4-Ph-Phenyl 1128 3 CONHMe 4-Ph-Phenyl 1129 1 SO₂Me 4-Ph-Phenyl 1130 2 SO₂Me 4-Ph-Phenyl 1131 3 SO₂Me 4-Ph-Phenyl 1132 1 SO₂NH₂ 4-Ph-Phenyl 1133 2 SO₂NH₂ 4-Ph-Phenyl 1134 3 SO₂NH₂ 4-Ph-Phenyl 1135 1 H 3-morpholino-phenyl 1136 2 H 3-morpholino-phenyl 1137 3 H 3-morpholino-phenyl 1138 1 Me 3-morpholino-phenyl 1139 2 Me 3-morpholino-phenyl 1140 3 Me 3-morpholino-phenyl 1141 1 CH₂Ph 3-morpholino-phenyl 1142 2 CH₂Ph 3-morpholino-phenyl 1143 3 CH₂Ph 3-morpholino-phenyl 1144 1 COMe 3-morpholino-phenyl 1145 2 COMe 3-morpholino-phenyl 1146 3 COMe 3-morpholino-phenyl 1147 1 CO₂Me 3-morpholino-phenyl 1148 2 CO₂Me 3-morpholino-phenyl 1149 3 CO₂Me 3-morpholino-phenyl 1150 1 CO₂tBu 3-morpholino-phenyl 1151 2 CO₂tBu 3-morpholino-phenyl 1152 3 CO₂tBu 3-morpholino-phenyl 1153 1 CONHMe 3-morpholino-phenyl 1154 2 CONHMe 3-morpholino-phenyl 1155 3 CONHMe 3-morpholino-phenyl 1156 1 SO₂Me 3-morpholino-phenyl 1157 2 SO₂Me 3-morpholino-phenyl 1158 3 SO₂Me 3-morpholino-phenyl 1159 1 SO₂NH₂ 3-morpholino-phenyl 1160 2 SO₂NH₂ 3-morpholino-phenyl 1161 3 SO₂NH₂ 3-morpholino-phenyl 1162 1 H 2-pyrazinyl 1163 2 H 2-pyrazinyl 1164 3 H 2-pyrazinyl 1165 1 Me 2-pyrazinyl 1166 2 Me 2-pyrazinyl 1167 3 Me 2-pyrazinyl 1168 1 CH₂Ph 2-pyrazinyl 1169 2 CH₂Ph 2-pyrazinyl 1170 3 CH₂Ph 2-pyrazinyl 1171 1 COMe 2-pyrazinyl 1172 2 COMe 2-pyrazinyl 1173 3 COMe 2-pyrazinyl 1174 1 CO₂Me 2-pyrazinyl 1175 2 CO₂Me 2-pyrazinyl 1176 3 CO₂Me 2-pyrazinyl 1177 1 CO₂tBu 2-pyrazinyl 1178 2 CO₂tBu 2-pyrazinyl 1179 3 CO₂tBu 2-pyrazinyl 1180 1 CONHMe 2-pyrazinyl 1181 2 CONHMe 2-pyrazinyl 1182 3 CONHMe 2-pyrazinyl 1183 1 SO₂Me 2-pyrazinyl 1184 2 SO₂Me 2-pyrazinyl 1185 3 SO₂Me 2-pyrazinyl 1186 1 SO₂NH₂ 2-pyrazinyl 1187 2 SO₂NH₂ 2-pyrazinyl 1188 3 SO₂NH₂ 2-pyrazinyl 1189 1 H 5-indolyl 1190 2 H 5-indolyl 1191 3 H 5-indolyl 1192 1 Me 5-indolyl 1193 2 Me 5-indolyl 1194 3 Me 5-indolyl 1195 1 CH₂Ph 5-indolyl 1196 2 CH₂Ph 5-indolyl 1197 3 CH₂Ph 5-indolyl 1198 1 COMe 5-indolyl 1199 2 COMe 5-indolyl 1200 3 COMe 5-indolyl 1201 1 CO₂Me 5-indolyl 1202 2 CO₂Me 5-indolyl 1203 3 CO₂Me 5-indolyl 1204 1 CO₂tBu 5-indolyl 1205 2 CO₂tBu 5-indolyl 1206 3 CO₂tBu 5-indolyl 1207 1 CONHMe 5-indolyl 1208 2 CONHMe 5-indolyl 1209 3 CONHMe 5-indolyl 1210 1 SO₂Me 5-indolyl 1211 2 SO₂Me 5-indolyl 1212 3 SO₂Me 5-indolyl 1213 1 SO₂NH₂ 5-indolyl 1214 2 SO₂NH₂ 5-indolyl 1215 3 SO₂NH₂ 5-indolyl 1216 1 H 1H-benzo[d]imidazol- 4-yl 1217 2 H 1H-benzo[d]imidazol- 4-yl 1218 3 H 1H-benzo[d]imidazol- 4-yl 1219 1 Me 1H-benzo[d]imidazol- 4-yl 1220 2 Me 1H-benzo[d]imidazol- 4-yl 1221 3 Me 1H-benzo[d]imidazol- 4-yl 1222 1 CH₂Ph 1H-benzo[d]imidazol- 4-yl 1223 2 CH₂Ph 1H-benzo[d]imidazol- 4-yl 1224 3 CH₂Ph 1H-benzo[d]imidazol- 4-yl 1225 1 COMe 1H-benzo[d]imidazol- 4-yl 1226 2 COMe 1H-benzo[d]imidazol- 4-yl 1227 3 COMe 1H-benzo[d]imidazol- 4-yl 1228 1 CO₂Me 1H-benzo[d]imidazol- 4-yl 1229 2 CO₂Me 1H-benzo[d]imidazol- 4-yl 1230 3 CO₂Me 1H-benzo[d]imidazol- 4-yl 1231 1 CO₂tBu 1H-benzo[d]imidazol- 4-yl 1232 2 CO₂tBu 1H-benzo[d]imidazol- 4-yl 1233 3 CO₂tBu 1H-benzo[d]imidazol- 4-yl 1234 1 CONHMe 1H-benzo[d]imidazol- 4-yl 1235 2 CONHMe 1H-benzo[d]imidazol- 4-yl 1236 3 CONHMe 1H-benzo[d]imidazol- 4-yl 1237 1 SO₂Me 1H-benzo[d]imidazol- 4-yl 1238 2 SO₂Me 1H-benzo[d]imidazol- 4-yl 1239 3 SO₂Me 1H-benzo[d]imidazol- 4-yl 1240 1 SO₂NH₂ 1H-benzo[d]imidazol- 4-yl 1241 2 SO₂NH₂ 1H-benzo[d]imidazol- 4-yl 1242 3 SO₂NH₂ 1H-benzo[d]imidazol- 4-yl

Exemplary embodiments include compounds having the formula (XIX)

or a pharmaceutically acceptable salt form thereof defined herein below in Table 3.

TABLE 3 Entry n R R^(1a) R^(1b) R^(1c) R^(1d) 1 1 H H H H H 2 2 H H H H H 3 3 H H H H H 4 1 Me H H H H 5 2 Me H H H H 6 3 Me H H H H 7 1 CH₂Ph H H H H 8 2 CH₂Ph H H H H 9 3 CH₂Ph H H H H 10 1 COMe H H H H 11 2 COMe H H H H 12 3 COMe H H H H 13 1 CO₂Me H H H H 14 2 CO₂Me H H H H 15 3 CO₂Me H H H H 16 1 CO₂tBu H H H H 17 2 CO₂tBu H H H H 18 3 CO₂tBu H H H H 19 1 CONHMe H H H H 20 2 CONHMe H H H H 21 3 CONHMe H H H H 22 1 SO₂Me H H H H 23 2 SO₂Me H H H H 24 3 SO₂Me H H H H 25 1 SO₂NH₂ H H H H 26 2 SO₂NH₂ H H H H 27 3 SO₂NH₂ H H H H 28 1 H H H OH H 29 2 H H H OH H 30 3 H H H OH H 31 1 Me H H OH H 32 2 Me H H OH H 33 3 Me H H OH H 34 1 CH₂Ph H H OH H 35 2 CH₂Ph H H OH H 36 3 CH₂Ph H H OH H 37 1 COMe H H OH H 38 2 COMe H H OH H 39 3 COMe H H OH H 40 1 CO₂Me H H OH H 41 2 CO₂Me H H OH H 42 3 CO₂Me H H OH H 43 1 CO₂tBu H H OH H 44 2 CO₂tBu H H OH H 45 3 CO₂tBu H H OH H 46 1 CONHMe H H OH H 47 2 CONHMe H H OH H 48 3 CONHMe H H OH H 49 1 SO₂Me H H OH H 50 2 SO₂Me H H OH H 51 3 SO₂Me H H OH H 52 1 SO₂NH₂ H H OH H 53 2 SO₂NH₂ H H OH H 54 3 SO₂NH₂ H H OH H 55 1 H H H OMe H 56 2 H H H OMe H 57 3 H H H OMe H 58 1 Me H H OMe H 59 2 Me H H OMe H 60 3 Me H H OMe H 61 1 CH₂Ph H H OMe H 62 2 CH₂Ph H H OMe H 63 3 CH₂Ph H H OMe H 64 1 COMe H H OMe H 65 2 COMe H H OMe H 66 3 COMe H H OMe H 67 1 CO₂Me H H OMe H 68 2 CO₂Me H H OMe H 69 3 CO₂Me H H OMe H 70 1 CO₂tBu H H OMe H 71 2 CO₂tBu H H OMe H 72 3 CO₂tBu H H OMe H 73 1 CONHMe H H OMe H 74 2 CONHMe H H OMe H 75 3 CONHMe H H OMe H 76 1 SO₂Me H H OMe H 77 2 SO₂Me H H OMe H 78 3 SO₂Me H H OMe H 79 1 SO₂NH₂ H H OMe H 80 2 SO₂NH₂ H H OMe H 81 3 SO₂NH₂ H H OMe H 82 1 H H H Me H 83 2 H H H Me H 84 3 H H H Me H 85 1 Me H H Me H 86 2 Me H H Me H 87 3 Me H H Me H 88 1 CH₂Ph H H Me H 89 2 CH₂Ph H H Me H 90 3 CH₂Ph H H Me H 91 1 COMe H H Me H 92 2 COMe H H Me H 93 3 COMe H H Me H 94 1 CO₂Me H H Me H 95 2 CO₂Me H H Me H 96 3 CO₂Me H H Me H 97 1 CO₂tBu H H Me H 98 2 CO₂tBu H H Me H 99 3 CO₂tBu H H Me H 100 1 CONHMe H H Me H 101 2 CONHMe H H Me H 102 3 CONHMe H H Me H 103 1 SO₂Me H H Me H 104 2 SO₂Me H H Me H 105 3 SO₂Me H H Me H 106 1 SO₂NH₂ H H Me H 107 2 SO₂NH₂ H H Me H 108 3 SO₂NH₂ H H Me H 109 1 H H H CF₃ H 110 2 H H H CF₃ H 111 3 H H H CF₃ H 112 1 Me H H CF₃ H 113 2 Me H H CF₃ H 114 3 Me H H CF₃ H 115 1 CH₂Ph H H CF₃ H 116 2 CH₂Ph H H CF₃ H 117 3 CH₂Ph H H CF₃ H 118 1 COMe H H CF₃ H 119 2 COMe H H CF₃ H 120 3 COMe H H CF₃ H 121 1 CO₂Me H H CF₃ H 122 2 CO₂Me H H CF₃ H 123 3 CO₂Me H H CF₃ H 124 1 CO₂tBu H H CF₃ H 125 2 CO₂tBu H H CF₃ H 126 3 CO₂tBu H H CF₃ H 127 1 CONHMe H H CF₃ H 128 2 CONHMe H H CF₃ H 129 3 CONHMe H H CF₃ H 130 1 SO₂Me H H CF₃ H 131 2 SO₂Me H H CF₃ H 132 3 SO₂Me H H CF₃ H 133 1 SO₂NH₂ H H CF₃ H 134 2 SO₂NH₂ H H CF₃ H 135 3 SO₂NH₂ H H CF₃ H 136 1 H H H F H 137 2 H H H F H 138 3 H H H F H 139 1 Me H H F H 140 2 Me H H F H 141 3 Me H H F H 142 1 CH₂Ph H H F H 143 2 CH₂Ph H H F H 144 3 CH₂Ph H H F H 145 1 COMe H H F H 146 2 COMe H H F H 147 3 COMe H H F H 148 1 CO₂Me H H F H 149 2 CO₂Me H H F H 150 3 CO₂Me H H F H 151 1 CO₂tBu H H F H 152 2 CO₂tBu H H F H 153 3 CO₂tBu H H F H 154 1 CONHMe H H F H 155 2 CONHMe H H F H 156 3 CONHMe H H F H 157 1 SO₂Me H H F H 158 2 SO₂Me H H F H 159 3 SO₂Me H H F H 160 1 SO₂NH₂ H H F H 161 2 SO₂NH₂ H H F H 162 3 SO₂NH₂ H H F H 163 1 H H H Cl H 164 2 H H H Cl H 165 3 H H H Cl H 166 1 Me H H Cl H 167 2 Me H H Cl H 168 3 Me H H Cl H 169 1 CH₂Ph H H Cl H 170 2 CH₂Ph H H Cl H 171 3 CH₂Ph H H Cl H 172 1 COMe H H Cl H 173 2 COMe H H Cl H 174 3 COMe H H Cl H 175 1 CO₂Me H H Cl H 176 2 CO₂Me H H Cl H 177 3 CO₂Me H H Cl H 178 1 CO₂tBu H H Cl H 179 2 CO₂tBu H H Cl H 180 3 CO₂tBu H H Cl H 181 1 CONHMe H H Cl H 182 2 CONHMe H H Cl H 183 3 CONHMe H H Cl H 184 1 SO₂Me H H Cl H 185 2 SO₂Me H H Cl H 186 3 SO₂Me H H Cl H 187 1 SO₂NH₂ H H Cl H 188 2 SO₂NH₂ H H Cl H 189 3 SO₂NH₂ H H Cl H 190 1 H H H CN H 191 2 H H H CN H 192 3 H H H CN H 193 1 Me H H CN H 194 2 Me H H CN H 195 3 Me H H CN H 196 1 CH₂Ph H H CN H 197 2 CH₂Ph H H CN H 198 3 CH₂Ph H H CN H 199 1 COMe H H CN H 200 2 COMe H H CN H 201 3 COMe H H CN H 202 1 CO₂Me H H CN H 203 2 CO₂Me H H CN H 204 3 CO₂Me H H CN H 205 1 CO₂tBu H H CN H 206 2 CO₂tBu H H CN H 207 3 CO₂tBu H H CN H 208 1 CONHMe H H CN H 209 2 CONHMe H H CN H 210 3 CONHMe H H CN H 211 1 SO₂Me H H CN H 212 2 SO₂Me H H CN H 213 3 SO₂Me H H CN H 214 1 SO₂NH₂ H H CN H 215 2 SO₂NH₂ H H CN H 216 3 SO₂NH₂ H H CN H 217 1 H H OH H H 218 2 H H OH H H 219 3 H H OH H H 220 1 Me H OH H H 221 2 Me H OH H H 222 3 Me H OH H H 223 1 CH₂Ph H OH H H 224 2 CH₂Ph H OH H H 225 3 CH₂Ph H OH H H 226 1 COMe H OH H H 227 2 COMe H OH H H 228 3 COMe H OH H H 229 1 CO₂Me H OH H H 230 2 CO₂Me H OH H H 231 3 CO₂Me H OH H H 232 1 CO₂tBu H OH H H 233 2 CO₂tBu H OH H H 234 3 CO₂tBu H OH H H 235 1 CONHMe H OH H H 236 2 CONHMe H OH H H 237 3 CONHMe H OH H H 238 1 SO₂Me H OH H H 239 2 SO₂Me H OH H H 240 3 SO₂Me H OH H H 241 1 SO₂NH₂ H OH H H 242 2 SO₂NH₂ H OH H H 243 3 SO₂NH₂ H OH H H 244 1 H H OMe H H 245 2 H H OMe H H 246 3 H H OMe H H 247 1 Me H OMe H H 248 2 Me H OMe H H 249 3 Me H OMe H H 250 1 CH₂Ph H OMe H H 251 2 CH₂Ph H OMe H H 252 3 CH₂Ph H OMe H H 253 1 COMe H OMe H H 254 2 COMe H OMe H H 255 3 COMe H OMe H H 256 1 CO₂Me H OMe H H 257 2 CO₂Me H OMe H H 258 3 CO₂Me H OMe H H 259 1 CO₂tBu H OMe H H 260 2 CO₂tBu H OMe H H 261 3 CO₂tBu H OMe H H 262 1 CONHMe H OMe H H 263 2 CONHMe H OMe H H 264 3 CONHMe H OMe H H 265 1 SO₂Me H OMe H H 266 2 SO₂Me H OMe H H 267 3 SO₂Me H OMe H H 268 1 SO₂NH₂ H OMe H H 269 2 SO₂NH₂ H OMe H H 270 3 SO₂NH₂ H OMe H H 271 1 H H Me H H 272 2 H H Me H H 273 3 H H Me H H 274 1 Me H Me H H 275 2 Me H Me H H 276 3 Me H Me H H 277 1 CH₂Ph H Me H H 278 2 CH₂Ph H Me H H 279 3 CH₂Ph H Me H H 280 1 COMe H Me H H 281 2 COMe H Me H H 282 3 COMe H Me H H 283 1 CO₂Me H Me H H 284 2 CO₂Me H Me H H 285 3 CO₂Me H Me H H 286 1 CO₂tBu H Me H H 287 2 CO₂tBu H Me H H 288 3 CO₂tBu H Me H H 289 1 CONHMe H Me H H 290 2 CONHMe H Me H H 291 3 CONHMe H Me H H 292 1 SO₂Me H Me H H 293 2 SO₂Me H Me H H 294 3 SO₂Me H Me H H 295 1 SO₂NH₂ H Me H H 296 2 SO₂NH₂ H Me H H 297 3 SO₂NH₂ H Me H H 298 1 H H CF₃ H H 299 2 H H CF₃ H H 300 3 H H CF₃ H H 301 1 Me H CF₃ H H 302 2 Me H CF₃ H H 303 3 Me H CF₃ H H 304 1 CH₂Ph H CF₃ H H 305 2 CH₂Ph H CF₃ H H 306 3 CH₂Ph H CF₃ H H 307 1 COMe H CF₃ H H 308 2 COMe H CF₃ H H 309 3 COMe H CF₃ H H 310 1 CO₂Me H CF₃ H H 311 2 CO₂Me H CF₃ H H 312 3 CO₂Me H CF₃ H H 313 1 CO₂tBu H CF₃ H H 314 2 CO₂tBu H CF₃ H H 315 3 CO₂tBu H CF₃ H H 316 1 CONHMe H CF₃ H H 317 2 CONHMe H CF₃ H H 318 3 CONHMe H CF₃ H H 319 1 SO₂Me H CF₃ H H 320 2 SO₂Me H CF₃ H H 321 3 SO₂Me H CF₃ H H 322 1 SO₂NH₂ H CF₃ H H 323 2 SO₂NH₂ H CF₃ H H 324 3 SO₂NH₂ H CF₃ H H 325 1 H H F H H 326 2 H H F H H 327 3 H H F H H 328 1 Me H F H H 329 2 Me H F H H 330 3 Me H F H H 331 1 CH₂Ph H F H H 332 2 CH₂Ph H F H H 333 3 CH₂Ph H F H H 334 1 COMe H F H H 335 2 COMe H F H H 336 3 COMe H F H H 337 1 CO₂Me H F H H 338 2 CO₂Me H F H H 339 3 CO₂Me H F H H 340 1 CO₂tBu H F H H 341 2 CO₂tBu H F H H 342 3 CO₂tBu H F H H 343 1 CONHMe H F H H 344 2 CONHMe H F H H 345 3 CONHMe H F H H 346 1 SO₂Me H F H H 347 2 SO₂Me H F H H 348 3 SO₂Me H F H H 349 1 SO₂NH₂ H F H H 350 2 SO₂NH₂ H F H H 351 3 SO₂NH₂ H F H H 352 1 H H Cl H H 353 2 H H Cl H H 354 3 H H Cl H H 355 1 Me H Cl H H 356 2 Me H Cl H H 357 3 Me H Cl H H 358 1 CH₂Ph H Cl H H 359 2 CH₂Ph H Cl H H 360 3 CH₂Ph H Cl H H 361 1 COMe H Cl H H 362 2 COMe H Cl H H 363 3 COMe H Cl H H 364 1 CO₂Me H Cl H H 365 2 CO₂Me H Cl H H 366 3 CO₂Me H Cl H H 367 1 CO₂tBu H Cl H H 368 2 CO₂tBu H Cl H H 369 3 CO₂tBu H Cl H H 370 1 CONHMe H Cl H H 371 2 CONHMe H Cl H H 372 3 CONHMe H Cl H H 373 1 SO₂Me H Cl H H 374 2 SO₂Me H Cl H H 375 3 SO₂Me H Cl H H 376 1 SO₂NH₂ H Cl H H 377 2 SO₂NH₂ H Cl H H 378 3 SO₂NH₂ H Cl H H 379 1 H H CN H H 380 2 H H CN H H 381 3 H H CN H H 382 1 Me H CN H H 383 2 Me H CN H H 384 3 Me H CN H H 385 1 CH₂Ph H CN H H 386 2 CH₂Ph H CN H H 387 3 CH₂Ph H CN H H 388 1 COMe H CN H H 389 2 COMe H CN H H 390 3 COMe H CN H H 391 1 CO₂Me H CN H H 392 2 CO₂Me H CN H H 393 3 CO₂Me H CN H H 394 1 CO₂tBu H CN H H 395 2 CO₂tBu H CN H H 396 3 CO₂tBu H CN H H 397 1 CONHMe H CN H H 398 2 CONHMe H CN H H 399 3 CONHMe H CN H H 400 1 SO₂Me H CN H H 401 2 SO₂Me H CN H H 402 3 SO₂Me H CN H H 403 1 SO₂NH₂ H CN H H 404 2 SO₂NH₂ H CN H H 405 3 SO₂NH₂ H CN H H

Exemplary embodiments include compounds having the formula (XX)

or a pharmaceutically acceptable salt form thereof defined herein below in Table 4.

TABLE 4 Entry n R R^(1a) R^(1b) R^(1c) R^(1d) 1 1 H H H H H 2 2 H H H H H 3 3 H H H H H 4 1 Me H H H H 5 2 Me H H H H 6 3 Me H H H H 7 1 CH₂Ph H H H H 8 2 CH₂Ph H H H H 9 3 CH₂Ph H H H H 10 1 COMe H H H H 11 2 COMe H H H H 12 3 COMe H H H H 13 1 CO₂Me H H H H 14 2 CO₂Me H H H H 15 3 CO₂Me H H H H 16 1 CO₂tBu H H H H 17 2 CO₂tBu H H H H 18 3 CO₂tBu H H H H 19 1 CONHMe H H H H 20 2 CONHMe H H H H 21 3 CONHMe H H H H 22 1 SO₂Me H H H H 23 2 SO₂Me H H H H 24 3 SO₂Me H H H H 25 1 SO₂NH₂ H H H H 26 2 SO₂NH₂ H H H H 27 3 SO₂NH₂ H H H H 28 1 H H H OH H 29 2 H H H OH H 30 3 H H H OH H 31 1 Me H H OH H 32 2 Me H H OH H 33 3 Me H H OH H 34 1 CH₂Ph H H OH H 35 2 CH₂Ph H H OH H 36 3 CH₂Ph H H OH H 37 1 COMe H H OH H 38 2 COMe H H OH H 39 3 COMe H H OH H 40 1 CO₂Me H H OH H 41 2 CO₂Me H H OH H 42 3 CO₂Me H H OH H 43 1 CO₂tBu H H OH H 44 2 CO₂tBu H H OH H 45 3 CO₂tBu H H OH H 46 1 CONHMe H H OH H 47 2 CONHMe H H OH H 48 3 CONHMe H H OH H 49 1 SO₂Me H H OH H 50 2 SO₂Me H H OH H 51 3 SO₂Me H H OH H 52 1 SO₂NH₂ H H OH H 53 2 SO₂NH₂ H H OH H 54 3 SO₂NH₂ H H OH H 55 1 H H H OMe H 56 2 H H H OMe H 57 3 H H H OMe H 58 1 Me H H OMe H 59 2 Me H H OMe H 60 3 Me H H OMe H 61 1 CH₂Ph H H OMe H 62 2 CH₂Ph H H OMe H 63 3 CH₂Ph H H OMe H 64 1 COMe H H OMe H 65 2 COMe H H OMe H 66 3 COMe H H OMe H 67 1 CO₂Me H H OMe H 68 2 CO₂Me H H OMe H 69 3 CO₂Me H H OMe H 70 1 CO₂tBu H H OMe H 71 2 CO₂tBu H H OMe H 72 3 CO₂tBu H H OMe H 73 1 CONHMe H H OMe H 74 2 CONHMe H H OMe H 75 3 CONHMe H H OMe H 76 1 SO₂Me H H OMe H 77 2 SO₂Me H H OMe H 78 3 SO₂Me H H OMe H 79 1 SO₂NH₂ H H OMe H 80 2 SO₂NH₂ H H OMe H 81 3 SO₂NH₂ H H OMe H 82 1 H H H Me H 83 2 H H H Me H 84 3 H H H Me H 85 1 Me H H Me H 86 2 Me H H Me H 87 3 Me H H Me H 88 1 CH₂Ph H H Me H 89 2 CH₂Ph H H Me H 90 3 CH₂Ph H H Me H 91 1 COMe H H Me H 92 2 COMe H H Me H 93 3 COMe H H Me H 94 1 CO₂Me H H Me H 95 2 CO₂Me H H Me H 96 3 CO₂Me H H Me H 97 1 CO₂tBu H H Me H 98 2 CO₂tBu H H Me H 99 3 CO₂tBu H H Me H 100 1 CONHMe H H Me H 101 2 CONHMe H H Me H 102 3 CONHMe H H Me H 103 1 SO₂Me H H Me H 104 2 SO₂Me H H Me H 105 3 SO₂Me H H Me H 106 1 SO₂NH₂ H H Me H 107 2 SO₂NH₂ H H Me H 108 3 SO₂NH₂ H H Me H 109 1 H H H CF₃ H 110 2 H H H CF₃ H 111 3 H H H CF₃ H 112 1 Me H H CF₃ H 113 2 Me H H CF₃ H 114 3 Me H H CF₃ H 115 1 CH₂Ph H H CF₃ H 116 2 CH₂Ph H H CF₃ H 117 3 CH₂Ph H H CF₃ H 118 1 COMe H H CF₃ H 119 2 COMe H H CF₃ H 120 3 COMe H H CF₃ H 121 1 CO₂Me H H CF₃ H 122 2 CO₂Me H H CF₃ H 123 3 CO₂Me H H CF₃ H 124 1 CO₂tBu H H CF₃ H 125 2 CO₂tBu H H CF₃ H 126 3 CO₂tBu H H CF₃ H 127 1 CONHMe H H CF₃ H 128 2 CONHMe H H CF₃ H 129 3 CONHMe H H CF₃ H 130 1 SO₂Me H H CF₃ H 131 2 SO₂Me H H CF₃ H 132 3 SO₂Me H H CF₃ H 133 1 SO₂NH₂ H H CF₃ H 134 2 SO₂NH₂ H H CF₃ H 135 3 SO₂NH₂ H H CF₃ H 136 1 H H H F H 137 2 H H H F H 138 3 H H H F H 139 1 Me H H F H 140 2 Me H H F H 141 3 Me H H F H 142 1 CH₂Ph H H F H 143 2 CH₂Ph H H F H 144 3 CH₂Ph H H F H 145 1 COMe H H F H 146 2 COMe H H F H 147 3 COMe H H F H 148 1 CO₂Me H H F H 149 2 CO₂Me H H F H 150 3 CO₂Me H H F H 151 1 CO₂tBu H H F H 152 2 CO₂tBu H H F H 153 3 CO₂tBu H H F H 154 1 CONHMe H H F H 155 2 CONHMe H H F H 156 3 CONHMe H H F H 157 1 SO₂Me H H F H 158 2 SO₂Me H H F H 159 3 SO₂Me H H F H 160 1 SO₂NH₂ H H F H 161 2 SO₂NH₂ H H F H 162 3 SO₂NH₂ H H F H 163 1 H H H Cl H 164 2 H H H Cl H 165 3 H H H Cl H 166 1 Me H H Cl H 167 2 Me H H Cl H 168 3 Me H H Cl H 169 1 CH₂Ph H H Cl H 170 2 CH₂Ph H H Cl H 171 3 CH₂Ph H H Cl H 172 1 COMe H H Cl H 173 2 COMe H H Cl H 174 3 COMe H H Cl H 175 1 CO₂Me H H Cl H 176 2 CO₂Me H H Cl H 177 3 CO₂Me H H Cl H 178 1 CO₂tBu H H Cl H 179 2 CO₂tBu H H Cl H 180 3 CO₂tBu H H Cl H 181 1 CONHMe H H Cl H 182 2 CONHMe H H Cl H 183 3 CONHMe H H Cl H 184 1 SO₂Me H H Cl H 185 2 SO₂Me H H Cl H 186 3 SO₂Me H H Cl H 187 1 SO₂NH₂ H H Cl H 188 2 SO₂NH₂ H H Cl H 189 3 SO₂NH₂ H H Cl H 190 1 H H H CN H 191 2 H H H CN H 192 3 H H H CN H 193 1 Me H H CN H 194 2 Me H H CN H 195 3 Me H H CN H 196 1 CH₂Ph H H CN H 197 2 CH₂Ph H H CN H 198 3 CH₂Ph H H CN H 199 1 COMe H H CN H 200 2 COMe H H CN H 201 3 COMe H H CN H 202 1 CO₂Me H H CN H 203 2 CO₂Me H H CN H 204 3 CO₂Me H H CN H 205 1 CO₂tBu H H CN H 206 2 CO₂tBu H H CN H 207 3 CO₂tBu H H CN H 208 1 CONHMe H H CN H 209 2 CONHMe H H CN H 210 3 CONHMe H H CN H 211 1 SO₂Me H H CN H 212 2 SO₂Me H H CN H 213 3 SO₂Me H H CN H 214 1 SO₂NH₂ H H CN H 215 2 SO₂NH₂ H H CN H 216 3 SO₂NH₂ H H CN H 217 1 H H OH H H 218 2 H H OH H H 219 3 H H OH H H 220 1 Me H OH H H 221 2 Me H OH H H 222 3 Me H OH H H 223 1 CH₂Ph H OH H H 224 2 CH₂Ph H OH H H 225 3 CH₂Ph H OH H H 226 1 COMe H OH H H 227 2 COMe H OH H H 228 3 COMe H OH H H 229 1 CO₂Me H OH H H 230 2 CO₂Me H OH H H 231 3 CO₂Me H OH H H 232 1 CO₂tBu H OH H H 233 2 CO₂tBu H OH H H 234 3 CO₂tBu H OH H H 235 1 CONHMe H OH H H 236 2 CONHMe H OH H H 237 3 CONHMe H OH H H 238 1 SO₂Me H OH H H 239 2 SO₂Me H OH H H 240 3 SO₂Me H OH H H 241 1 SO₂NH₂ H OH H H 242 2 SO₂NH₂ H OH H H 243 3 SO₂NH₂ H OH H H 244 1 H H OMe H H 245 2 H H OMe H H 246 3 H H OMe H H 247 1 Me H OMe H H 248 2 Me H OMe H H 249 3 Me H OMe H H 250 1 CH₂Ph H OMe H H 251 2 CH₂Ph H OMe H H 252 3 CH₂Ph H OMe H H 253 1 COMe H OMe H H 254 2 COMe H OMe H H 255 3 COMe H OMe H H 256 1 CO₂Me H OMe H H 257 2 CO₂Me H OMe H H 258 3 CO₂Me H OMe H H 259 1 CO₂tBu H OMe H H 260 2 CO₂tBu H OMe H H 261 3 CO₂tBu H OMe H H 262 1 CONHMe H OMe H H 263 2 CONHMe H OMe H H 264 3 CONHMe H OMe H H 265 1 SO₂Me H OMe H H 266 2 SO₂Me H OMe H H 267 3 SO₂Me H OMe H H 268 1 SO₂NH₂ H OMe H H 269 2 SO₂NH₂ H OMe H H 270 3 SO₂NH₂ H OMe H H 271 1 H H Me H H 272 2 H H Me H H 273 3 H H Me H H 274 1 Me H Me H H 275 2 Me H Me H H 276 3 Me H Me H H 277 1 CH₂Ph H Me H H 278 2 CH₂Ph H Me H H 279 3 CH₂Ph H Me H H 280 1 COMe H Me H H 281 2 COMe H Me H H 282 3 COMe H Me H H 283 1 CO₂Me H Me H H 284 2 CO₂Me H Me H H 285 3 CO₂Me H Me H H 286 1 CO₂tBu H Me H H 287 2 CO₂tBu H Me H H 288 3 CO₂tBu H Me H H 289 1 CONHMe H Me H H 290 2 CONHMe H Me H H 291 3 CONHMe H Me H H 292 1 SO₂Me H Me H H 293 2 SO₂Me H Me H H 294 3 SO₂Me H Me H H 295 1 SO₂NH₂ H Me H H 296 2 SO₂NH₂ H Me H H 297 3 SO₂NH₂ H Me H H 298 1 H H CF₃ H H 299 2 H H CF₃ H H 300 3 H H CF₃ H H 301 1 Me H CF₃ H H 302 2 Me H CF₃ H H 303 3 Me H CF₃ H H 304 1 CH₂Ph H CF₃ H H 305 2 CH₂Ph H CF₃ H H 306 3 CH₂Ph H CF₃ H H 307 1 COMe H CF₃ H H 308 2 COMe H CF₃ H H 309 3 COMe H CF₃ H H 310 1 CO₂Me H CF₃ H H 311 2 CO₂Me H CF₃ H H 312 3 CO₂Me H CF₃ H H 313 1 CO₂tBu H CF₃ H H 314 2 CO₂tBu H CF₃ H H 315 3 CO₂tBu H CF₃ H H 316 1 CONHMe H CF₃ H H 317 2 CONHMe H CF₃ H H 318 3 CONHMe H CF₃ H H 319 1 SO₂Me H CF₃ H H 320 2 SO₂Me H CF₃ H H 321 3 SO₂Me H CF₃ H H 322 1 SO₂NH₂ H CF₃ H H 323 2 SO₂NH₂ H CF₃ H H 324 3 SO₂NH₂ H CF₃ H H 325 1 H H F H H 326 2 H H F H H 327 3 H H F H H 328 1 Me H F H H 329 2 Me H F H H 330 3 Me H F H H 331 1 CH₂Ph H F H H 332 2 CH₂Ph H F H H 333 3 CH₂Ph H F H H 334 1 COMe H F H H 335 2 COMe H F H H 336 3 COMe H F H H 337 1 CO₂Me H F H H 338 2 CO₂Me H F H H 339 3 CO₂Me H F H H 340 1 CO₂tBu H F H H 341 2 CO₂tBu H F H H 342 3 CO₂tBu H F H H 343 1 CONHMe H F H H 344 2 CONHMe H F H H 345 3 CONHMe H F H H 346 1 SO₂Me H F H H 347 2 SO₂Me H F H H 348 3 SO₂Me H F H H 349 1 SO₂NH₂ H F H H 350 2 SO₂NH₂ H F H H 351 3 SO₂NH₂ H F H H 352 1 H H Cl H H 353 2 H H Cl H H 354 3 H H Cl H H 355 1 Me H Cl H H 356 2 Me H Cl H H 357 3 Me H Cl H H 358 1 CH₂Ph H Cl H H 359 2 CH₂Ph H Cl H H 360 3 CH₂Ph H Cl H H 361 1 COMe H Cl H H 362 2 COMe H Cl H H 363 3 COMe H Cl H H 364 1 CO₂Me H Cl H H 365 2 CO₂Me H Cl H H 366 3 CO₂Me H Cl H H 367 1 CO₂tBu H Cl H H 368 2 CO₂tBu H Cl H H 369 3 CO₂tBu H Cl H H 370 1 CONHMe H Cl H H 371 2 CONHMe H Cl H H 372 3 CONHMe H Cl H H 373 1 SO₂Me H Cl H H 374 2 SO₂Me H Cl H H 375 3 SO₂Me H Cl H H 376 1 SO₂NH₂ H Cl H H 377 2 SO₂NH₂ H Cl H H 378 3 SO₂NH₂ H Cl H H 379 1 H H CN H H 380 2 H H CN H H 381 3 H H CN H H 382 1 Me H CN H H 383 2 Me H CN H H 384 3 Me H CN H H 385 1 CH₂Ph H CN H H 386 2 CH₂Ph H CN H H 387 3 CH₂Ph H CN H H 388 1 COMe H CN H H 389 2 COMe H CN H H 390 3 COMe H CN H H 391 1 CO₂Me H CN H H 392 2 CO₂Me H CN H H 393 3 CO₂Me H CN H H 394 1 CO₂tBu H CN H H 395 2 CO₂tBu H CN H H 396 3 CO₂tBu H CN H H 397 1 CONHMe H CN H H 398 2 CONHMe H CN H H 399 3 CONHMe H CN H H 400 1 SO₂Me H CN H H 401 2 SO₂Me H CN H H 402 3 SO₂Me H CN H H 403 1 SO₂NH₂ H CN H H 404 2 SO₂NH₂ H CN H H 405 3 SO₂NH₂ H CN H H

Exemplary embodiments include compounds having the formula (XXI)

or a pharmaceutically acceptable salt form thereof defined herein below in Table 5.

TABLE 5 Entry n R R^(1a) R^(1b) R^(1c) R^(1d) 1 1 H H H H H 2 2 H H H H H 3 3 H H H H H 4 1 Me H H H H 5 2 Me H H H H 6 3 Me H H H H 7 1 CH₂Ph H H H H 8 2 CH₂Ph H H H H 9 3 CH₂Ph H H H H 10 1 COMe H H H H 11 2 COMe H H H H 12 3 COMe H H H H 13 1 CO₂Me H H H H 14 2 CO₂Me H H H H 15 3 CO₂Me H H H H 16 1 CO₂tBu H H H H 17 2 CO₂tBu H H H H 18 3 CO₂tBu H H H H 19 1 CONHMe H H H H 20 2 CONHMe H H H H 21 3 CONHMe H H H H 22 1 SO₂Me H H H H 23 2 SO₂Me H H H H 24 3 SO₂Me H H H H 25 1 SO₂NH₂ H H H H 26 2 SO₂NH₂ H H H H 27 3 SO₂NH₂ H H H H

Exemplary embodiments include compounds having the formula (XXII)

or a pharmaceutically acceptable salt form thereof defined herein below in Table 6.

TABLE 6 Entry n R R^(1a) R^(1b) R^(1c) R^(1d) 1 1 H H H H H 2 2 H H H H H 3 3 H H H H H 4 1 Me H H H H 5 2 Me H H H H 6 3 Me H H H H 7 1 CH₂Ph H H H H 8 2 CH₂Ph H H H H 9 3 CH₂Ph H H H H 10 1 COMe H H H H 11 2 COMe H H H H 12 3 COMe H H H H 13 1 CO₂Me H H H H 14 2 CO₂Me H H H H 15 3 CO₂Me H H H H 16 1 CO₂tBu H H H H 17 2 CO₂tBu H H H H 18 3 CO₂tBu H H H H 19 1 CONHMe H H H H 20 2 CONHMe H H H H 21 3 CONHMe H H H H 22 1 SO₂Me H H H H 23 2 SO₂Me H H H H 24 3 SO₂Me H H H H 25 1 SO₂NH₂ H H H H 26 2 SO₂NH₂ H H H H 27 3 SO₂NH₂ H H H H

Exemplary embodiments include compounds having the formula (XXIII)

or a pharmaceutically acceptable salt form thereof defined herein below in Table 7.

TABLE 7 Entry n X R³ Entry n R R³ 1 1 O Phenyl 277 1 O 4-OH-Phenyl 2 2 O Phenyl 278 2 O 4-OH-Phenyl 3 3 O Phenyl 279 3 O 4-OH-Phenyl 4 1 S Phenyl 280 1 S 4-OH-Phenyl 5 2 S Phenyl 281 2 S 4-OH-Phenyl 6 3 S Phenyl 282 3 S 4-OH-Phenyl 7 1 SO Phenyl 283 1 SO 4-OH-Phenyl 8 2 SO Phenyl 284 2 SO 4-OH-Phenyl 9 3 SO Phenyl 285 3 SO 4-OH-Phenyl 10 1 SO₂ Phenyl 286 1 SO₂ 4-OH-Phenyl 11 2 SO₂ Phenyl 287 2 SO₂ 4-OH-Phenyl 12 3 SO₂ Phenyl 288 3 SO₂ 4-OH-Phenyl 13 1 O 3-OH-Phenyl 289 1 O 2-OH-Phenyl 14 2 O 3-OH-Phenyl 290 2 O 2-OH-Phenyl 15 3 O 3-OH-Phenyl 291 3 O 2-OH-Phenyl 16 1 S 3-OH-Phenyl 292 1 S 2-OH-Phenyl 17 2 S 3-OH-Phenyl 293 2 S 2-OH-Phenyl 18 3 S 3-OH-Phenyl 294 3 S 2-OH-Phenyl 19 1 SO 3-OH-Phenyl 295 1 SO 2-OH-Phenyl 20 2 SO 3-OH-Phenyl 296 2 SO 2-OH-Phenyl 21 3 SO 3-OH-Phenyl 297 3 SO 2-OH-Phenyl 22 1 SO₂ 3-OH-Phenyl 298 1 SO₂ 2-OH-Phenyl 23 2 SO₂ 3-OH-Phenyl 299 2 SO₂ 2-OH-Phenyl 24 3 SO₂ 3-OH-Phenyl 300 3 SO₂ 2-OH-Phenyl 25 1 O 4-NO₂-Phenyl 301 1 O 4-OMe-Phenyl 26 2 O 4-NO₂-Phenyl 302 2 O 4-OMe-Phenyl 27 3 O 4-NO₂-Phenyl 303 3 O 4-OMe-Phenyl 28 1 S 4-NO₂-Phenyl 304 1 S 4-OMe-Phenyl 29 2 S 4-NO₂-Phenyl 305 2 S 4-OMe-Phenyl 30 3 S 4-NO₂-Phenyl 306 3 S 4-OMe-Phenyl 31 1 SO 4-NO₂-Phenyl 307 1 SO 4-OMe-Phenyl 32 2 SO 4-NO₂-Phenyl 308 2 SO 4-OMe-Phenyl 33 3 SO 4-NO₂-Phenyl 309 3 SO 4-OMe-Phenyl 34 1 SO₂ 4-NO₂-Phenyl 310 1 SO₂ 4-OMe-Phenyl 35 2 SO₂ 4-NO₂-Phenyl 311 2 SO₂ 4-OMe-Phenyl 36 3 SO₂ 4-NO₂-Phenyl 312 3 SO₂ 4-OMe-Phenyl 37 1 O 3-OMe-Phenyl 313 1 O 2-OMe-Phenyl 38 2 O 3-OMe-Phenyl 314 2 O 2-OMe-Phenyl 39 3 O 3-OMe-Phenyl 315 3 O 2-OMe-Phenyl 40 1 S 3-OMe-Phenyl 316 1 S 2-OMe-Phenyl 41 2 S 3-OMe-Phenyl 317 2 S 2-OMe-Phenyl 42 3 S 3-OMe-Phenyl 318 3 S 2-OMe-Phenyl 43 1 SO 3-OMe-Phenyl 319 1 SO 2-OMe-Phenyl 44 2 SO 3-OMe-Phenyl 320 2 SO 2-OMe-Phenyl 45 3 SO 3-OMe-Phenyl 321 3 SO 2-OMe-Phenyl 46 1 SO₂ 3-OMe-Phenyl 322 1 SO₂ 2-OMe-Phenyl 47 2 SO₂ 3-OMe-Phenyl 323 2 SO₂ 2-OMe-Phenyl 48 3 SO₂ 3-OMe-Phenyl 324 3 SO₂ 2-OMe-Phenyl 49 1 O 4-CN-Phenyl 325 1 O 3-CN-Phenyl 50 2 O 4-CN-Phenyl 326 2 O 3-CN-Phenyl 51 3 O 4-CN-Phenyl 327 3 O 3-CN-Phenyl 52 1 S 4-CN-Phenyl 328 1 S 3-CN-Phenyl 53 2 S 4-CN-Phenyl 329 2 S 3-CN-Phenyl 54 3 S 4-CN-Phenyl 330 3 S 3-CN-Phenyl 55 1 SO 4-CN-Phenyl 331 1 SO 3-CN-Phenyl 56 2 SO 4-CN-Phenyl 332 2 SO 3-CN-Phenyl 57 3 SO 4-CN-Phenyl 333 3 SO 3-CN-Phenyl 58 1 SO₂ 4-CN-Phenyl 334 1 SO₂ 3-CN-Phenyl 59 2 SO₂ 4-CN-Phenyl 335 2 SO₂ 3-CN-Phenyl 60 3 SO₂ 4-CN-Phenyl 336 3 SO₂ 3-CN-Phenyl 61 1 O 2-CN-Phenyl 337 1 O 2-Me-Phenyl 62 2 O 2-CN-Phenyl 338 2 O 2-Me-Phenyl 63 3 O 2-CN-Phenyl 339 3 O 2-Me-Phenyl 64 1 S 2-CN-Phenyl 340 1 S 2-Me-Phenyl 65 2 S 2-CN-Phenyl 341 2 S 2-Me-Phenyl 66 3 S 2-CN-Phenyl 342 3 S 2-Me-Phenyl 67 1 SO 2-CN-Phenyl 343 1 SO 2-Me-Phenyl 68 2 SO 2-CN-Phenyl 344 2 SO 2-Me-Phenyl 69 3 SO 2-CN-Phenyl 345 3 SO 2-Me-Phenyl 70 1 SO₂ 2-CN-Phenyl 346 1 SO₂ 2-Me-Phenyl 71 2 SO₂ 2-CN-Phenyl 347 2 SO₂ 2-Me-Phenyl 72 3 SO₂ 2-CN-Phenyl 348 3 SO₂ 2-Me-Phenyl 73 1 O 3-Me-Phenyl 349 1 O 4-Me-Phenyl 74 2 O 3-Me-Phenyl 350 2 O 4-Me-Phenyl 75 3 O 3-Me-Phenyl 351 3 O 4-Me-Phenyl 76 1 S 3-Me-Phenyl 352 1 S 4-Me-Phenyl 77 2 S 3-Me-Phenyl 353 2 S 4-Me-Phenyl 78 3 S 3-Me-Phenyl 354 3 S 4-Me-Phenyl 79 1 SO 3-Me-Phenyl 355 1 SO 4-Me-Phenyl 80 2 SO 3-Me-Phenyl 356 2 SO 4-Me-Phenyl 81 3 SO 3-Me-Phenyl 357 3 SO 4-Me-Phenyl 82 1 SO₂ 3-Me-Phenyl 358 1 SO₂ 4-Me-Phenyl 83 2 SO₂ 3-Me-Phenyl 359 2 SO₂ 4-Me-Phenyl 84 3 SO₂ 3-Me-Phenyl 360 3 SO₂ 4-Me-Phenyl 85 1 O 2-F-Phenyl 361 1 O 3-F-Phenyl 86 2 O 2-F-Phenyl 362 2 O 3-F-Phenyl 87 3 O 2-F-Phenyl 363 3 O 3-F-Phenyl 88 1 S 2-F-Phenyl 364 1 S 3-F-Phenyl 89 2 S 2-F-Phenyl 365 2 S 3-F-Phenyl 90 3 S 2-F-Phenyl 366 3 S 3-F-Phenyl 91 1 SO 2-F-Phenyl 367 1 SO 3-F-Phenyl 92 2 SO 2-F-Phenyl 368 2 SO 3-F-Phenyl 93 3 SO 2-F-Phenyl 369 3 SO 3-F-Phenyl 94 1 SO₂ 2-F-Phenyl 370 1 SO₂ 3-F-Phenyl 95 2 SO₂ 2-F-Phenyl 371 2 SO₂ 3-F-Phenyl 96 3 SO₂ 2-F-Phenyl 372 3 SO₂ 3-F-Phenyl 97 1 O 4-F-Phenyl 373 1 O 2-Cl-Phenyl 98 2 O 4-F-Phenyl 374 2 O 2-Cl-Phenyl 99 3 O 4-F-Phenyl 375 3 O 2-Cl-Phenyl 100 1 S 4-F-Phenyl 376 1 S 2-Cl-Phenyl 101 2 S 4-F-Phenyl 377 2 S 2-Cl-Phenyl 102 3 S 4-F-Phenyl 378 3 S 2-Cl-Phenyl 103 1 SO 4-F-Phenyl 379 1 SO 2-Cl-Phenyl 104 2 SO 4-F-Phenyl 380 2 SO 2-Cl-Phenyl 105 3 SO 4-F-Phenyl 381 3 SO 2-Cl-Phenyl 106 1 SO₂ 4-F-Phenyl 382 1 SO₂ 2-Cl-Phenyl 107 2 SO₂ 4-F-Phenyl 383 2 SO₂ 2-Cl-Phenyl 108 3 SO₂ 4-F-Phenyl 384 3 SO₂ 2-Cl-Phenyl 109 1 O 3-Cl-Phenyl 385 1 O 4-Cl-Phenyl 110 2 O 3-Cl-Phenyl 386 2 O 4-Cl-Phenyl 111 3 O 3-Cl-Phenyl 387 3 O 4-Cl-Phenyl 112 1 S 3-Cl-Phenyl 388 1 S 4-Cl-Phenyl 113 2 S 3-Cl-Phenyl 389 2 S 4-Cl-Phenyl 114 3 S 3-Cl-Phenyl 390 3 S 4-Cl-Phenyl 115 1 SO 3-Cl-Phenyl 391 1 SO 4-Cl-Phenyl 116 2 SO 3-Cl-Phenyl 392 2 SO 4-Cl-Phenyl 117 3 SO 3-Cl-Phenyl 393 3 SO 4-Cl-Phenyl 118 1 SO₂ 3-Cl-Phenyl 394 1 SO₂ 4-Cl-Phenyl 119 2 SO₂ 3-Cl-Phenyl 395 2 SO₂ 4-Cl-Phenyl 120 3 SO₂ 3-Cl-Phenyl 396 3 SO₂ 4-Cl-Phenyl 121 1 O 2-Br-Phenyl 397 1 O 3-Br-Phenyl 122 2 O 2-Br-Phenyl 398 2 O 3-Br-Phenyl 123 3 O 2-Br-Phenyl 399 3 O 3-Br-Phenyl 124 1 S 2-Br-Phenyl 400 1 S 3-Br-Phenyl 125 2 S 2-Br-Phenyl 401 2 S 3-Br-Phenyl 126 3 S 2-Br-Phenyl 402 3 S 3-Br-Phenyl 127 1 SO 2-Br-Phenyl 403 1 SO 3-Br-Phenyl 128 2 SO 2-Br-Phenyl 404 2 SO 3-Br-Phenyl 129 3 SO 2-Br-Phenyl 405 3 SO 3-Br-Phenyl 130 1 SO₂ 2-Br-Phenyl 406 1 SO₂ 3-Br-Phenyl 131 2 SO₂ 2-Br-Phenyl 407 2 SO₂ 3-Br-Phenyl 132 3 SO₂ 2-Br-Phenyl 408 3 SO₂ 3-Br-Phenyl 133 1 O 4-Br-Phenyl 409 1 O 2-CF₃-Phenyl 134 2 O 4-Br-Phenyl 410 2 O 2-CF₃-Phenyl 135 3 O 4-Br-Phenyl 411 3 O 2-CF₃-Phenyl 136 1 S 4-Br-Phenyl 412 1 S 2-CF₃-Phenyl 137 2 S 4-Br-Phenyl 413 2 S 2-CF₃-Phenyl 138 3 S 4-Br-Phenyl 414 3 S 2-CF₃-Phenyl 139 1 SO 4-Br-Phenyl 415 1 SO 2-CF₃-Phenyl 140 2 SO 4-Br-Phenyl 416 2 SO 2-CF₃-Phenyl 141 3 SO 4-Br-Phenyl 417 3 SO 2-CF₃-Phenyl 142 1 SO₂ 4-Br-Phenyl 418 1 SO₂ 2-CF₃-Phenyl 143 2 SO₂ 4-Br-Phenyl 419 2 SO₂ 2-CF₃-Phenyl 144 3 SO₂ 4-Br-Phenyl 420 3 SO₂ 2-CF₃-Phenyl 145 1 O 3-CF₃-Phenyl 421 1 O 4-CF₃-Phenyl 146 2 O 3-CF₃-Phenyl 422 2 O 4-CF₃-Phenyl 147 3 O 3-CF₃-Phenyl 423 3 O 4-CF₃-Phenyl 148 1 S 3-CF₃-Phenyl 424 1 S 4-CF₃-Phenyl 149 2 S 3-CF₃-Phenyl 425 2 S 4-CF₃-Phenyl 150 3 S 3-CF₃-Phenyl 426 3 S 4-CF₃-Phenyl 151 1 SO 3-CF₃-Phenyl 427 1 SO 4-CF₃-Phenyl 152 2 SO 3-CF₃-Phenyl 428 2 SO 4-CF₃-Phenyl 153 3 SO 3-CF₃-Phenyl 429 3 SO 4-CF₃-Phenyl 154 1 SO₂ 3-CF₃-Phenyl 430 1 SO₂ 4-CF₃-Phenyl 155 2 SO₂ 3-CF₃-Phenyl 431 2 SO₂ 4-CF₃-Phenyl 156 3 SO₂ 3-CF₃-Phenyl 432 3 SO₂ 4-CF₃-Phenyl 157 1 O 2-iPr-Phenyl 433 1 O 3-iPr-Phenyl 158 2 O 2-iPr-Phenyl 434 2 O 3-iPr-Phenyl 159 3 O 2-iPr-Phenyl 435 3 O 3-iPr-Phenyl 160 1 S 2-iPr-Phenyl 436 1 S 3-iPr-Phenyl 161 2 S 2-iPr-Phenyl 437 2 S 3-iPr-Phenyl 162 3 S 2-iPr-Phenyl 438 3 S 3-iPr-Phenyl 163 1 SO 2-iPr-Phenyl 439 1 SO 3-iPr-Phenyl 164 2 SO 2-iPr-Phenyl 440 2 SO 3-iPr-Phenyl 165 3 SO 2-iPr-Phenyl 441 3 SO 3-iPr-Phenyl 166 1 SO₂ 2-iPr-Phenyl 442 1 SO₂ 3-iPr-Phenyl 167 2 SO₂ 2-iPr-Phenyl 443 2 SO₂ 3-iPr-Phenyl 168 3 SO₂ 2-iPr-Phenyl 444 3 SO₂ 3-iPr-Phenyl 169 1 O 4-iPr-Phenyl 445 1 O 4-NH₂-Phenyl 170 2 O 4-iPr-Phenyl 446 2 O 4-NH₂-Phenyl 171 3 O 4-iPr-Phenyl 447 3 O 4-NH₂-Phenyl 172 1 S 4-iPr-Phenyl 448 1 S 4-NH₂-Phenyl 173 2 S 4-iPr-Phenyl 449 2 S 4-NH₂-Phenyl 174 3 S 4-iPr-Phenyl 450 3 S 4-NH₂-Phenyl 175 1 SO 4-iPr-Phenyl 451 1 SO 4-NH₂-Phenyl 176 2 SO 4-iPr-Phenyl 452 2 SO 4-NH₂-Phenyl 177 3 SO 4-iPr-Phenyl 453 3 SO 4-NH₂-Phenyl 178 1 SO₂ 4-iPr-Phenyl 454 1 SO₂ 4-NH₂-Phenyl 179 2 SO₂ 4-iPr-Phenyl 455 2 SO₂ 4-NH₂-Phenyl 180 3 SO₂ 4-iPr-Phenyl 456 3 SO₂ 4-NH₂-Phenyl 181 1 O 3-NH₂-Phenyl 457 1 O 2-NH₂-Phenyl 182 2 O 3-NH₂-Phenyl 458 2 O 2-NH₂-Phenyl 183 3 O 3-NH₂-Phenyl 459 3 O 2-NH₂-Phenyl 184 1 S 3-NH₂-Phenyl 460 1 S 2-NH₂-Phenyl 185 2 S 3-NH₂-Phenyl 461 2 S 2-NH₂-Phenyl 186 3 S 3-NH₂-Phenyl 462 3 S 2-NH₂-Phenyl 187 1 SO 3-NH₂-Phenyl 463 1 SO 2-NH₂-Phenyl 188 2 SO 3-NH₂-Phenyl 464 2 SO 2-NH₂-Phenyl 189 3 SO 3-NH₂-Phenyl 465 3 SO 2-NH₂-Phenyl 190 1 SO₂ 3-NH₂-Phenyl 466 1 SO₂ 2-NH₂-Phenyl 191 2 SO₂ 3-NH₂-Phenyl 467 2 SO₂ 2-NH₂-Phenyl 192 3 SO₂ 3-NH₂-Phenyl 468 3 SO₂ 2-NH₂-Phenyl 193 1 O 2,4-di-Me-Phenyl 469 1 O 2,6-di-Me-Phenyl 194 2 O 2,4-di-Me-Phenyl 470 2 O 2,6-di-Me-Phenyl 195 3 O 2,4-di-Me-Phenyl 471 3 O 2,6-di-Me-Phenyl 196 1 S 2,4-di-Me-Phenyl 472 1 S 2,6-di-Me-Phenyl 197 2 S 2,4-di-Me-Phenyl 473 2 S 2,6-di-Me-Phenyl 198 3 S 2,4-di-Me-Phenyl 474 3 S 2,6-di-Me-Phenyl 199 1 SO 2,4-di-Me-Phenyl 475 1 SO 2,6-di-Me-Phenyl 200 2 SO 2,4-di-Me-Phenyl 476 2 SO 2,6-di-Me-Phenyl 201 3 SO 2,4-di-Me-Phenyl 477 3 SO 2,6-di-Me-Phenyl 202 1 SO₂ 2,4-di-Me-Phenyl 478 1 SO₂ 2,6-di-Me-Phenyl 203 2 SO₂ 2,4-di-Me-Phenyl 479 2 SO₂ 2,6-di-Me-Phenyl 204 3 SO₂ 2,4-di-Me-Phenyl 480 3 SO₂ 2,6-di-Me-Phenyl 205 1 O 2,6-di-iPr-Phenyl 481 1 O 2-Ph-Phenyl 206 2 O 2,6-di-iPr-Phenyl 482 2 O 2-Ph-Phenyl 207 3 O 2,6-di-iPr-Phenyl 483 3 O 2-Ph-Phenyl 208 1 S 2,6-di-iPr-Phenyl 484 1 S 2-Ph-Phenyl 209 2 S 2,6-di-iPr-Phenyl 485 2 S 2-Ph-Phenyl 210 3 S 2,6-di-iPr-Phenyl 486 3 S 2-Ph-Phenyl 211 1 SO 2,6-di-iPr-Phenyl 487 1 SO 2-Ph-Phenyl 212 2 SO 2,6-di-iPr-Phenyl 488 2 SO 2-Ph-Phenyl 213 3 SO 2,6-di-iPr-Phenyl 489 3 SO 2-Ph-Phenyl 214 1 SO₂ 2,6-di-iPr-Phenyl 490 1 SO₂ 2-Ph-Phenyl 215 2 SO₂ 2,6-di-iPr-Phenyl 491 2 SO₂ 2-Ph-Phenyl 216 3 SO₂ 2,6-di-iPr-Phenyl 492 3 SO₂ 2-Ph-Phenyl 217 1 O 3-Ph-Phenyl 493 1 O 4-Ph-Phenyl 218 2 O 3-Ph-Phenyl 494 2 O 4-Ph-Phenyl 219 3 O 3-Ph-Phenyl 495 3 O 4-Ph-Phenyl 220 1 S 3-Ph-Phenyl 496 1 S 4-Ph-Phenyl 221 2 S 3-Ph-Phenyl 497 2 S 4-Ph-Phenyl 222 3 S 3-Ph-Phenyl 498 3 S 4-Ph-Phenyl 223 1 SO 3-Ph-Phenyl 499 1 SO 4-Ph-Phenyl 224 2 SO 3-Ph-Phenyl 500 2 SO 4-Ph-Phenyl 225 3 SO 3-Ph-Phenyl 501 3 SO 4-Ph-Phenyl 226 1 SO₂ 3-Ph-Phenyl 502 1 SO₂ 4-Ph-Phenyl 227 2 SO₂ 3-Ph-Phenyl 503 2 SO₂ 4-Ph-Phenyl 228 3 SO₂ 3-Ph-Phenyl 504 3 SO₂ 4-Ph-Phenyl 229 1 O 2-morpholino-phenyl 505 1 O 3-morpholino-phenyl 230 2 O 2-morpholino-phenyl 506 2 O 3-morpholino-phenyl 231 3 O 2-morpholino-phenyl 507 3 O 3-morpholino-phenyl 232 1 S 2-morpholino-phenyl 508 1 S 3-morpholino-phenyl 233 2 S 2-morpholino-phenyl 509 2 S 3-morpholino-phenyl 234 3 S 2-morpholino-phenyl 510 3 S 3-morpholino-phenyl 235 1 SO 2-morpholino-phenyl 511 1 SO 3-morpholino-phenyl 236 2 SO 2-morpholino-phenyl 512 2 SO 3-morpholino-phenyl 237 3 SO 2-morpholino-phenyl 513 3 SO 3-morpholino-phenyl 238 1 SO₂ 2-morpholino-phenyl 514 1 SO₂ 3-morpholino-phenyl 239 2 SO₂ 2-morpholino-phenyl 515 2 SO₂ 3-morpholino-phenyl 240 3 SO₂ 2-morpholino-phenyl 516 3 SO₂ 3-morpholino-phenyl 241 1 O 4-morpholino-phenyl 517 1 O 2-pyrazinyl 242 2 O 4-morpholino-phenyl 518 2 O 2-pyrazinyl 243 3 O 4-morpholino-phenyl 519 3 O 2-pyrazinyl 244 1 S 4-morpholino-phenyl 520 1 S 2-pyrazinyl 245 2 S 4-morpholino-phenyl 521 2 S 2-pyrazinyl 246 3 S 4-morpholino-phenyl 522 3 S 2-pyrazinyl 247 1 SO 4-morpholino-phenyl 523 1 SO 2-pyrazinyl 248 2 SO 4-morpholino-phenyl 524 2 SO 2-pyrazinyl 249 3 SO 4-morpholino-phenyl 525 3 SO 2-pyrazinyl 250 1 SO₂ 4-morpholino-phenyl 526 1 SO₂ 2-pyrazinyl 251 2 SO₂ 4-morpholino-phenyl 527 2 SO₂ 2-pyrazinyl 252 3 SO₂ 4-morpholino-phenyl 528 3 SO₂ 2-pyrazinyl 253 1 O 2-pyrimidinyl 529 1 O 5-indolyl 254 2 O 2-pyrimidinyl 530 2 O 5-indolyl 255 3 O 2-pyrimidinyl 531 3 O 5-indolyl 256 1 S 2-pyrimidinyl 532 1 S 5-indolyl 257 2 S 2-pyrimidinyl 533 2 S 5-indolyl 258 3 S 2-pyrimidinyl 534 3 S 5-indolyl 259 1 SO 2-pyrimidinyl 535 1 SO 5-indolyl 260 2 SO 2-pyrimidinyl 536 2 SO 5-indolyl 261 3 SO 2-pyrimidinyl 537 3 SO 5-indolyl 262 1 SO₂ 2-pyrimidinyl 538 1 SO₂ 5-indolyl 263 2 SO₂ 2-pyrimidinyl 539 2 SO₂ 5-indolyl 264 3 SO₂ 2-pyrimidinyl 540 3 SO₂ 5-indolyl 265 1 O 2-methyl-1H- 541 1 O 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 266 2 O 2-methyl-1H- 542 2 O 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 267 3 O 2-methyl-1H- 543 3 O 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 268 1 S 2-methyl-1H- 544 1 S 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 269 2 S 2-methyl-1H- 545 2 S 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 270 3 S 2-methyl-1H- 546 3 S 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 271 1 SO 2-methyl-1H- 547 1 SO 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 272 2 SO 2-methyl-1H- 548 2 SO 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 273 3 SO 2-methyl-1H- 549 3 SO 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 274 1 SO₂ 2-methyl-1H- 550 1 SO₂ 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 275 2 SO₂ 2-methyl-1H- 551 2 SO₂ 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 276 3 SO₂ 2-methyl-1H- 552 3 SO₂ 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl

Exemplary embodiments include compounds having the formula (XXIV)

or a pharmaceutically acceptable salt form thereof defined herein below in Table 8.

TABLE 8 Entry n X R³ Entry n R R³ 1 1 O Phenyl 277 1 O 4-OH-Phenyl 2 2 O Phenyl 278 2 O 4-OH-Phenyl 3 3 O Phenyl 279 3 O 4-OH-Phenyl 4 1 S Phenyl 280 1 S 4-OH-Phenyl 5 2 S Phenyl 281 2 S 4-OH-Phenyl 6 3 S Phenyl 282 3 S 4-OH-Phenyl 7 1 SO Phenyl 283 1 SO 4-OH-Phenyl 8 2 SO Phenyl 284 2 SO 4-OH-Phenyl 9 3 SO Phenyl 285 3 SO 4-OH-Phenyl 10 1 SO₂ Phenyl 286 1 SO₂ 4-OH-Phenyl 11 2 SO₂ Phenyl 287 2 SO₂ 4-OH-Phenyl 12 3 SO₂ Phenyl 288 3 SO₂ 4-OH-Phenyl 13 1 O 3-OH-Phenyl 289 1 O 2-OH-Phenyl 14 2 O 3-OH-Phenyl 290 2 O 2-OH-Phenyl 15 3 O 3-OH-Phenyl 291 3 O 2-OH-Phenyl 16 1 S 3-OH-Phenyl 292 1 S 2-OH-Phenyl 17 2 S 3-OH-Phenyl 293 2 S 2-OH-Phenyl 18 3 S 3-OH-Phenyl 294 3 S 2-OH-Phenyl 19 1 SO 3-OH-Phenyl 295 1 SO 2-OH-Phenyl 20 2 SO 3-OH-Phenyl 296 2 SO 2-OH-Phenyl 21 3 SO 3-OH-Phenyl 297 3 SO 2-OH-Phenyl 22 1 SO₂ 3-OH-Phenyl 298 1 SO₂ 2-OH-Phenyl 23 2 SO₂ 3-OH-Phenyl 299 2 SO₂ 2-OH-Phenyl 24 3 SO₂ 3-OH-Phenyl 300 3 SO₂ 2-OH-Phenyl 25 1 O 4-NO₂-Phenyl 301 1 O 4-OMe-Phenyl 26 2 O 4-NO₂-Phenyl 302 2 O 4-OMe-Phenyl 27 3 O 4-NO₂-Phenyl 303 3 O 4-OMe-Phenyl 28 1 S 4-NO₂-Phenyl 304 1 S 4-OMe-Phenyl 29 2 S 4-NO₂-Phenyl 305 2 S 4-OMe-Phenyl 30 3 S 4-NO₂-Phenyl 306 3 S 4-OMe-Phenyl 31 1 SO 4-NO₂-Phenyl 307 1 SO 4-OMe-Phenyl 32 2 SO 4-NO₂-Phenyl 308 2 SO 4-OMe-Phenyl 33 3 SO 4-NO₂-Phenyl 309 3 SO 4-OMe-Phenyl 34 1 SO₂ 4-NO₂-Phenyl 310 1 SO₂ 4-OMe-Phenyl 35 2 SO₂ 4-NO₂-Phenyl 311 2 SO₂ 4-OMe-Phenyl 36 3 SO₂ 4-NO₂-Phenyl 312 3 SO₂ 4-OMe-Phenyl 37 1 O 3-OMe-Phenyl 313 1 O 2-OMe-Phenyl 38 2 O 3-OMe-Phenyl 314 2 O 2-OMe-Phenyl 39 3 O 3-OMe-Phenyl 315 3 O 2-OMe-Phenyl 40 1 S 3-OMe-Phenyl 316 1 S 2-OMe-Phenyl 41 2 S 3-OMe-Phenyl 317 2 S 2-OMe-Phenyl 42 3 S 3-OMe-Phenyl 318 3 S 2-OMe-Phenyl 43 1 SO 3-OMe-Phenyl 319 1 SO 2-OMe-Phenyl 44 2 SO 3-OMe-Phenyl 320 2 SO 2-OMe-Phenyl 45 3 SO 3-OMe-Phenyl 321 3 SO 2-OMe-Phenyl 46 1 SO₂ 3-OMe-Phenyl 322 1 SO₂ 2-OMe-Phenyl 47 2 SO₂ 3-OMe-Phenyl 323 2 SO₂ 2-OMe-Phenyl 48 3 SO₂ 3-OMe-Phenyl 324 3 SO₂ 2-OMe-Phenyl 49 1 O 4-CN-Phenyl 325 1 O 3-CN-Phenyl 50 2 O 4-CN-Phenyl 326 2 O 3-CN-Phenyl 51 3 O 4-CN-Phenyl 327 3 O 3-CN-Phenyl 52 1 S 4-CN-Phenyl 328 1 S 3-CN-Phenyl 53 2 S 4-CN-Phenyl 329 2 S 3-CN-Phenyl 54 3 S 4-CN-Phenyl 330 3 S 3-CN-Phenyl 55 1 SO 4-CN-Phenyl 331 1 SO 3-CN-Phenyl 56 2 SO 4-CN-Phenyl 332 2 SO 3-CN-Phenyl 57 3 SO 4-CN-Phenyl 333 3 SO 3-CN-Phenyl 58 1 SO₂ 4-CN-Phenyl 334 1 SO₂ 3-CN-Phenyl 59 2 SO₂ 4-CN-Phenyl 335 2 SO₂ 3-CN-Phenyl 60 3 SO₂ 4-CN-Phenyl 336 3 SO₂ 3-CN-Phenyl 61 1 O 2-CN-Phenyl 337 1 O 2-Me-Phenyl 62 2 O 2-CN-Phenyl 338 2 O 2-Me-Phenyl 63 3 O 2-CN-Phenyl 339 3 O 2-Me-Phenyl 64 1 S 2-CN-Phenyl 340 1 S 2-Me-Phenyl 65 2 S 2-CN-Phenyl 341 2 S 2-Me-Phenyl 66 3 S 2-CN-Phenyl 342 3 S 2-Me-Phenyl 67 1 SO 2-CN-Phenyl 343 1 SO 2-Me-Phenyl 68 2 SO 2-CN-Phenyl 344 2 SO 2-Me-Phenyl 69 3 SO 2-CN-Phenyl 345 3 SO 2-Me-Phenyl 70 1 SO₂ 2-CN-Phenyl 346 1 SO₂ 2-Me-Phenyl 71 2 SO₂ 2-CN-Phenyl 347 2 SO₂ 2-Me-Phenyl 72 3 SO₂ 2-CN-Phenyl 348 3 SO₂ 2-Me-Phenyl 73 1 O 3-Me-Phenyl 349 1 O 4-Me-Phenyl 74 2 O 3-Me-Phenyl 350 2 O 4-Me-Phenyl 75 3 O 3-Me-Phenyl 351 3 O 4-Me-Phenyl 76 1 S 3-Me-Phenyl 352 1 S 4-Me-Phenyl 77 2 S 3-Me-Phenyl 353 2 S 4-Me-Phenyl 78 3 S 3-Me-Phenyl 354 3 S 4-Me-Phenyl 79 1 SO 3-Me-Phenyl 355 1 SO 4-Me-Phenyl 80 2 SO 3-Me-Phenyl 356 2 SO 4-Me-Phenyl 81 3 SO 3-Me-Phenyl 357 3 SO 4-Me-Phenyl 82 1 SO₂ 3-Me-Phenyl 358 1 SO₂ 4-Me-Phenyl 83 2 SO₂ 3-Me-Phenyl 359 2 SO₂ 4-Me-Phenyl 84 3 SO₂ 3-Me-Phenyl 360 3 SO₂ 4-Me-Phenyl 85 1 O 2-F-Phenyl 361 1 O 3-F-Phenyl 86 2 O 2-F-Phenyl 362 2 O 3-F-Phenyl 87 3 O 2-F-Phenyl 363 3 O 3-F-Phenyl 88 1 S 2-F-Phenyl 364 1 S 3-F-Phenyl 89 2 S 2-F-Phenyl 365 2 S 3-F-Phenyl 90 3 S 2-F-Phenyl 366 3 S 3-F-Phenyl 91 1 SO 2-F-Phenyl 367 1 SO 3-F-Phenyl 92 2 SO 2-F-Phenyl 368 2 SO 3-F-Phenyl 93 3 SO 2-F-Phenyl 369 3 SO 3-F-Phenyl 94 1 SO₂ 2-F-Phenyl 370 1 SO₂ 3-F-Phenyl 95 2 SO₂ 2-F-Phenyl 371 2 SO₂ 3-F-Phenyl 96 3 SO₂ 2-F-Phenyl 372 3 SO₂ 3-F-Phenyl 97 1 O 4-F-Phenyl 373 1 O 2-Cl-Phenyl 98 2 O 4-F-Phenyl 374 2 O 2-Cl-Phenyl 99 3 O 4-F-Phenyl 375 3 O 2-Cl-Phenyl 100 1 S 4-F-Phenyl 376 1 S 2-Cl-Phenyl 101 2 S 4-F-Phenyl 377 2 S 2-Cl-Phenyl 102 3 S 4-F-Phenyl 378 3 S 2-Cl-Phenyl 103 1 SO 4-F-Phenyl 379 1 SO 2-Cl-Phenyl 104 2 SO 4-F-Phenyl 380 2 SO 2-Cl-Phenyl 105 3 SO 4-F-Phenyl 381 3 SO 2-Cl-Phenyl 106 1 SO₂ 4-F-Phenyl 382 1 SO₂ 2-Cl-Phenyl 107 2 SO₂ 4-F-Phenyl 383 2 SO₂ 2-Cl-Phenyl 108 3 SO₂ 4-F-Phenyl 384 3 SO₂ 2-Cl-Phenyl 109 1 O 3-Cl-Phenyl 385 1 O 4-Cl-Phenyl 110 2 O 3-Cl-Phenyl 386 2 O 4-Cl-Phenyl 111 3 O 3-Cl-Phenyl 387 3 O 4-Cl-Phenyl 112 1 S 3-Cl-Phenyl 388 1 S 4-Cl-Phenyl 113 2 S 3-Cl-Phenyl 389 2 S 4-Cl-Phenyl 114 3 S 3-Cl-Phenyl 390 3 S 4-Cl-Phenyl 115 1 SO 3-Cl-Phenyl 391 1 SO 4-Cl-Phenyl 116 2 SO 3-Cl-Phenyl 392 2 SO 4-Cl-Phenyl 117 3 SO 3-Cl-Phenyl 393 3 SO 4-Cl-Phenyl 118 1 SO₂ 3-Cl-Phenyl 394 1 SO₂ 4-Cl-Phenyl 119 2 SO₂ 3-Cl-Phenyl 395 2 SO₂ 4-Cl-Phenyl 120 3 SO₂ 3-Cl-Phenyl 396 3 SO₂ 4-Cl-Phenyl 121 1 O 2-Br-Phenyl 397 1 O 3-Br-Phenyl 122 2 O 2-Br-Phenyl 398 2 O 3-Br-Phenyl 123 3 O 2-Br-Phenyl 399 3 O 3-Br-Phenyl 124 1 S 2-Br-Phenyl 400 1 S 3-Br-Phenyl 125 2 S 2-Br-Phenyl 401 2 S 3-Br-Phenyl 126 3 S 2-Br-Phenyl 402 3 S 3-Br-Phenyl 127 1 SO 2-Br-Phenyl 403 1 SO 3-Br-Phenyl 128 2 SO 2-Br-Phenyl 404 2 SO 3-Br-Phenyl 129 3 SO 2-Br-Phenyl 405 3 SO 3-Br-Phenyl 130 1 SO₂ 2-Br-Phenyl 406 1 SO₂ 3-Br-Phenyl 131 2 SO₂ 2-Br-Phenyl 407 2 SO₂ 3-Br-Phenyl 132 3 SO₂ 2-Br-Phenyl 408 3 SO₂ 3-Br-Phenyl 133 1 O 4-Br-Phenyl 409 1 O 2-CF₃-Phenyl 134 2 O 4-Br-Phenyl 410 2 O 2-CF₃-Phenyl 135 3 O 4-Br-Phenyl 411 3 O 2-CF₃-Phenyl 136 1 S 4-Br-Phenyl 412 1 S 2-CF₃-Phenyl 137 2 S 4-Br-Phenyl 413 2 S 2-CF₃-Phenyl 138 3 S 4-Br-Phenyl 414 3 S 2-CF₃-Phenyl 139 1 SO 4-Br-Phenyl 415 1 SO 2-CF₃-Phenyl 140 2 SO 4-Br-Phenyl 416 2 SO 2-CF₃-Phenyl 141 3 SO 4-Br-Phenyl 417 3 SO 2-CF₃-Phenyl 142 1 SO₂ 4-Br-Phenyl 418 1 SO₂ 2-CF₃-Phenyl 143 2 SO₂ 4-Br-Phenyl 419 2 SO₂ 2-CF₃-Phenyl 144 3 SO₂ 4-Br-Phenyl 420 3 SO₂ 2-CF₃-Phenyl 145 1 O 3-CF₃-Phenyl 421 1 O 4-CF₃-Phenyl 146 2 O 3-CF₃-Phenyl 422 2 O 4-CF₃-Phenyl 147 3 O 3-CF₃-Phenyl 423 3 O 4-CF₃-Phenyl 148 1 S 3-CF₃-Phenyl 424 1 S 4-CF₃-Phenyl 149 2 S 3-CF₃-Phenyl 425 2 S 4-CF₃-Phenyl 150 3 S 3-CF₃-Phenyl 426 3 S 4-CF₃-Phenyl 151 1 SO 3-CF₃-Phenyl 427 1 SO 4-CF₃-Phenyl 152 2 SO 3-CF₃-Phenyl 428 2 SO 4-CF₃-Phenyl 153 3 SO 3-CF₃-Phenyl 429 3 SO 4-CF₃-Phenyl 154 1 SO₂ 3-CF₃-Phenyl 430 1 SO₂ 4-CF₃-Phenyl 155 2 SO₂ 3-CF₃-Phenyl 431 2 SO₂ 4-CF₃-Phenyl 156 3 SO₂ 3-CF₃-Phenyl 432 3 SO₂ 4-CF₃-Phenyl 157 1 O 2-iPr-Phenyl 433 1 O 3-iPr-Phenyl 158 2 O 2-iPr-Phenyl 434 2 O 3-iPr-Phenyl 159 3 O 2-iPr-Phenyl 435 3 O 3-iPr-Phenyl 160 1 S 2-iPr-Phenyl 436 1 S 3-iPr-Phenyl 161 2 S 2-iPr-Phenyl 437 2 S 3-iPr-Phenyl 162 3 S 2-iPr-Phenyl 438 3 S 3-iPr-Phenyl 163 1 SO 2-iPr-Phenyl 439 1 SO 3-iPr-Phenyl 164 2 SO 2-iPr-Phenyl 440 2 SO 3-iPr-Phenyl 165 3 SO 2-iPr-Phenyl 441 3 SO 3-iPr-Phenyl 166 1 SO₂ 2-iPr-Phenyl 442 1 SO₂ 3-iPr-Phenyl 167 2 SO₂ 2-iPr-Phenyl 443 2 SO₂ 3-iPr-Phenyl 168 3 SO₂ 2-iPr-Phenyl 444 3 SO₂ 3-iPr-Phenyl 169 1 O 4-iPr-Phenyl 445 1 O 4-NH₂-Phenyl 170 2 O 4-iPr-Phenyl 446 2 O 4-NH₂-Phenyl 171 3 O 4-iPr-Phenyl 447 3 O 4-NH₂-Phenyl 172 1 S 4-iPr-Phenyl 448 1 S 4-NH₂-Phenyl 173 2 S 4-iPr-Phenyl 449 2 S 4-NH₂-Phenyl 174 3 S 4-iPr-Phenyl 450 3 S 4-NH₂-Phenyl 175 1 SO 4-iPr-Phenyl 451 1 SO 4-NH₂-Phenyl 176 2 SO 4-iPr-Phenyl 452 2 SO 4-NH₂-Phenyl 177 3 SO 4-iPr-Phenyl 453 3 SO 4-NH₂-Phenyl 178 1 SO₂ 4-iPr-Phenyl 454 1 SO₂ 4-NH₂-Phenyl 179 2 SO₂ 4-iPr-Phenyl 455 2 SO₂ 4-NH₂-Phenyl 180 3 SO₂ 4-iPr-Phenyl 456 3 SO₂ 4-NH₂-Phenyl 181 1 O 3-NH₂-Phenyl 457 1 O 2-NH₂-Phenyl 182 2 O 3-NH₂-Phenyl 458 2 O 2-NH₂-Phenyl 183 3 O 3-NH₂-Phenyl 459 3 O 2-NH₂-Phenyl 184 1 S 3-NH₂-Phenyl 460 1 S 2-NH₂-Phenyl 185 2 S 3-NH₂-Phenyl 461 2 S 2-NH₂-Phenyl 186 3 S 3-NH₂-Phenyl 462 3 S 2-NH₂-Phenyl 187 1 SO 3-NH₂-Phenyl 463 1 SO 2-NH₂-Phenyl 188 2 SO 3-NH₂-Phenyl 464 2 SO 2-NH₂-Phenyl 189 3 SO 3-NH₂-Phenyl 465 3 SO 2-NH₂-Phenyl 190 1 SO₂ 3-NH₂-Phenyl 466 1 SO₂ 2-NH₂-Phenyl 191 2 SO₂ 3-NH₂-Phenyl 467 2 SO₂ 2-NH₂-Phenyl 192 3 SO₂ 3-NH₂-Phenyl 468 3 SO₂ 2-NH₂-Phenyl 193 1 O 2,4-di-Me-Phenyl 469 1 O 2,6-di-Me-Phenyl 194 2 O 2,4-di-Me-Phenyl 470 2 O 2,6-di-Me-Phenyl 195 3 O 2,4-di-Me-Phenyl 471 3 O 2,6-di-Me-Phenyl 196 1 S 2,4-di-Me-Phenyl 472 1 S 2,6-di-Me-Phenyl 197 2 S 2,4-di-Me-Phenyl 473 2 S 2,6-di-Me-Phenyl 198 3 S 2,4-di-Me-Phenyl 474 3 S 2,6-di-Me-Phenyl 199 1 SO 2,4-di-Me-Phenyl 475 1 SO 2,6-di-Me-Phenyl 200 2 SO 2,4-di-Me-Phenyl 476 2 SO 2,6-di-Me-Phenyl 201 3 SO 2,4-di-Me-Phenyl 477 3 SO 2,6-di-Me-Phenyl 202 1 SO₂ 2,4-di-Me-Phenyl 478 1 SO₂ 2,6-di-Me-Phenyl 203 2 SO₂ 2,4-di-Me-Phenyl 479 2 SO₂ 2,6-di-Me-Phenyl 204 3 SO₂ 2,4-di-Me-Phenyl 480 3 SO₂ 2,6-di-Me-Phenyl 205 1 O 2,6-di-iPr-Phenyl 481 1 O 2-Ph-Phenyl 206 2 O 2,6-di-iPr-Phenyl 482 2 O 2-Ph-Phenyl 207 3 O 2,6-di-iPr-Phenyl 483 3 O 2-Ph-Phenyl 208 1 S 2,6-di-iPr-Phenyl 484 1 S 2-Ph-Phenyl 209 2 S 2,6-di-iPr-Phenyl 485 2 S 2-Ph-Phenyl 210 3 S 2,6-di-iPr-Phenyl 486 3 S 2-Ph-Phenyl 211 1 SO 2,6-di-iPr-Phenyl 487 1 SO 2-Ph-Phenyl 212 2 SO 2,6-di-iPr-Phenyl 488 2 SO 2-Ph-Phenyl 213 3 SO 2,6-di-iPr-Phenyl 489 3 SO 2-Ph-Phenyl 214 1 SO₂ 2,6-di-iPr-Phenyl 490 1 SO₂ 2-Ph-Phenyl 215 2 SO₂ 2,6-di-iPr-Phenyl 491 2 SO₂ 2-Ph-Phenyl 216 3 SO₂ 2,6-di-iPr-Phenyl 492 3 SO₂ 2-Ph-Phenyl 217 1 O 3-Ph-Phenyl 493 1 O 4-Ph-Phenyl 218 2 O 3-Ph-Phenyl 494 2 O 4-Ph-Phenyl 219 3 O 3-Ph-Phenyl 495 3 O 4-Ph-Phenyl 220 1 S 3-Ph-Phenyl 496 1 S 4-Ph-Phenyl 221 2 S 3-Ph-Phenyl 497 2 S 4-Ph-Phenyl 222 3 S 3-Ph-Phenyl 498 3 S 4-Ph-Phenyl 223 1 SO 3-Ph-Phenyl 499 1 SO 4-Ph-Phenyl 224 2 SO 3-Ph-Phenyl 500 2 SO 4-Ph-Phenyl 225 3 SO 3-Ph-Phenyl 501 3 SO 4-Ph-Phenyl 226 1 SO₂ 3-Ph-Phenyl 502 1 SO₂ 4-Ph-Phenyl 227 2 SO₂ 3-Ph-Phenyl 503 2 SO₂ 4-Ph-Phenyl 228 3 SO₂ 3-Ph-Phenyl 504 3 SO₂ 4-Ph-Phenyl 229 1 O 2-morpholino-phenyl 505 1 O 3-morpholino-phenyl 230 2 O 2-morpholino-phenyl 506 2 O 3-morpholino-phenyl 231 3 O 2-morpholino-phenyl 507 3 O 3-morpholino-phenyl 232 1 S 2-morpholino-phenyl 508 1 S 3-morpholino-phenyl 233 2 S 2-morpholino-phenyl 509 2 S 3-morpholino-phenyl 234 3 S 2-morpholino-phenyl 510 3 S 3-morpholino-phenyl 235 1 SO 2-morpholino-phenyl 511 1 SO 3-morpholino-phenyl 236 2 SO 2-morpholino-phenyl 512 2 SO 3-morpholino-phenyl 237 3 SO 2-morpholino-phenyl 513 3 SO 3-morpholino-phenyl 238 1 SO₂ 2-morpholino-phenyl 514 1 SO₂ 3-morpholino-phenyl 239 2 SO₂ 2-morpholino-phenyl 515 2 SO₂ 3-morpholino-phenyl 240 3 SO₂ 2-morpholino-phenyl 516 3 SO₂ 3-morpholino-phenyl 241 1 O 4-morpholino-phenyl 517 1 O 2-pyrazinyl 242 2 O 4-morpholino-phenyl 518 2 O 2-pyrazinyl 243 3 O 4-morpholino-phenyl 519 3 O 2-pyrazinyl 244 1 S 4-morpholino-phenyl 520 1 S 2-pyrazinyl 245 2 S 4-morpholino-phenyl 521 2 S 2-pyrazinyl 246 3 S 4-morpholino-phenyl 522 3 S 2-pyrazinyl 247 1 SO 4-morpholino-phenyl 523 1 SO 2-pyrazinyl 248 2 SO 4-morpholino-phenyl 524 2 SO 2-pyrazinyl 249 3 SO 4-morpholino-phenyl 525 3 SO 2-pyrazinyl 250 1 SO₂ 4-morpholino-phenyl 526 1 SO₂ 2-pyrazinyl 251 2 SO₂ 4-morpholino-phenyl 527 2 SO₂ 2-pyrazinyl 252 3 SO₂ 4-morpholino-phenyl 528 3 SO₂ 2-pyrazinyl 253 1 O 2-pyrimidinyl 529 1 O 5-indolyl 254 2 O 2-pyrimidinyl 530 2 O 5-indolyl 255 3 O 2-pyrimidinyl 531 3 O 5-indolyl 256 1 S 2-pyrimidinyl 532 1 S 5-indolyl 257 2 S 2-pyrimidinyl 533 2 S 5-indolyl 258 3 S 2-pyrimidinyl 534 3 S 5-indolyl 259 1 SO 2-pyrimidinyl 535 1 SO 5-indolyl 260 2 SO 2-pyrimidinyl 536 2 SO 5-indolyl 261 3 SO 2-pyrimidinyl 537 3 SO 5-indolyl 262 1 SO₂ 2-pyrimidinyl 538 1 SO₂ 5-indolyl 263 2 SO₂ 2-pyrimidinyl 539 2 SO₂ 5-indolyl 264 3 SO₂ 2-pyrimidinyl 540 3 SO₂ 5-indolyl 265 1 O 2-methyl-1H- 541 1 O 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 266 2 O 2-methyl-1H- 542 2 O 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 267 3 O 2-methyl-1H- 543 3 O 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 268 1 S 2-methyl-1H- 544 1 S 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 269 2 S 2-methyl-1H- 545 2 S 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 270 3 S 2-methyl-1H- 546 3 S 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 271 1 SO 2-methyl-1H- 547 1 SO 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 272 2 SO 2-methyl-1H- 548 2 SO 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 273 3 SO 2-methyl-1H- 549 3 SO 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 274 1 SO₂ 2-methyl-1H- 550 1 SO₂ 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 275 2 SO₂ 2-methyl-1H- 551 2 SO₂ 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl 276 3 SO₂ 2-methyl-1H- 552 3 SO₂ 1H-benzo[d]imidazol- benzo[d]imidazol-4-yl 4-yl

Exemplary embodiments include compounds having the formula (XXV)

or a pharmaceutically acceptable salt form thereof defined herein below in Table 9

TABLE 9 Entry R^(2d) R³ 1 ethyl 4-CH₃-phenyl 2 n-propyl 4-CH₃-phenyl 3 isopropyl 4-CH₃-phenyl 4 —CH₂CH(CH₃)₂ 4-CH₃-phenyl 5 CF₃ 4-CH₃-phenyl 6 —CH₂ CF₃ 4-CH₃-phenyl 7 —CH₂CH₂CF₃ 4-CH₃-phenyl 8 cyclopropyl 4-CH₃-phenyl 9 Cyclobutyl 4-CH₃-phenyl 10 cyclopentyl 4-CH₃-phenyl 11 cyclohexyl 4-CH₃-phenyl 12 3-pyridyl 4-CH₃-phenyl 13 1-methyl-1H- 4-CH₃-phenyl pyrazol-4-yl 14 1H-imidazol-4-yl 4-CH₃-phenyl 15 2-furanyl 4-CH₃-phenyl 16 ethyl 3-CH₃-phenyl 17 n-propyl 3-CH₃-phenyl 18 isopropyl 3-CH₃-phenyl 19 —CH₂CH(CH₃)₂ 3-CH₃-phenyl 20 —CF₃ 3-CH₃-phenyl 21 —CH₂CF₃ 3-CH₃-phenyl 22 —CH₂CH₂CF₃ 3-CH₃-phenyl 23 cyclopropyl 3-CH₃-phenyl 24 Cyclobutyl 3-CH₃-phenyl 25 cyclopentyl 3-CH₃-phenyl 26 cyclohexyl 3-CH₃-phenyl 27 3-pyridyl 3-CH₃-phenyl 28 1-methyl-1H- 3-CH₃-phenyl pyrazol-4-yl 29 1H-imidazol-4-yl 3-CH₃-phenyl 30 2-furanyl 3-CH₃-phenyl 31 ethyl 3-OH-Phenyl 32 n-propyl 3-OH-Phenyl 33 isopropyl 3-OH-Phenyl 34 —CH₂CH(CH₃)₂ 3-OH-Phenyl 35 —CF₃ 3-OH-Phenyl 36 —CH₂CF₃ 3-OH-Phenyl 37 —CH₂CH₂CF₃ 3-OH-Phenyl 38 cyclopropyl 3-OH-Phenyl 39 Cyclobutyl 3-OH-Phenyl 40 cyclopentyl 3-OH-Phenyl 41 cyclohexyl 3-OH-Phenyl 42 3-pyridyl 3-OH-Phenyl 43 1-methyl-1H- 3-OH-Phenyl pyrazol-4-yl 44 1H-imidazol-4-yl 3-OH-Phenyl 45 2-furanyl 3-OH-Phenyl 46 ethyl 4-OMe-Phenyl 47 n-propyl 4-OMe-Phenyl 48 isopropyl 4-OMe-Phenyl 49 —CH₂CH(CH₃)₂ 4-OMe-Phenyl 50 —CF₃ 4-OMe-Phenyl 51 —CH₂CF₃ 4-OMe-Phenyl 52 —CH₂CH₂CF₃ 4-OMe-Phenyl 53 cyclopropyl 4-OMe-Phenyl 54 Cyclobutyl 4-OMe-Phenyl 55 cyclopentyl 4-OMe-Phenyl 56 cyclohexyl 4-OMe-Phenyl 57 3-pyridyl 4-OMe-Phenyl 58 1-methyl-1H- 4-OMe-Phenyl pyrazol-4-yl 59 1H-imidazol-4-yl 4-OMe-Phenyl 60 2-furanyl 4-OMe-Phenyl 61 ethyl 2-OMe-Phenyl 62 n-propyl 2-OMe-Phenyl 63 isopropyl 2-OMe-Phenyl 64 —CH₂CH(CH₃)₂ 2-OMe-Phenyl 65 —CF₃ 2-OMe-Phenyl 66 —CH₂CF₃ 2-OMe-Phenyl 67 —CH₂CH₂CF₃ 2-OMe-Phenyl 68 cyclopropyl 2-OMe-Phenyl 69 Cyclobutyl 2-OMe-Phenyl 70 cyclopentyl 2-OMe-Phenyl 71 cyclohexyl 2-OMe-Phenyl 72 3-pyridyl 2-OMe-Phenyl 73 1-methyl-1H- 2-OMe-Phenyl pyrazol-4-yl 74 1H-imidazol-4-yl 2-OMe-Phenyl 75 2-furanyl 2-OMe-Phenyl 76 ethyl 3-CN-Phenyl 77 n-propyl 3-CN-Phenyl 78 isopropyl 3-CN-Phenyl 79 —CH₂CH(CH₃)₂ 3-CN-Phenyl 80 —CF₃ 3-CN-Phenyl 81 —CH₂CF₃ 3-CN-Phenyl 82 —CH₂CH₂CF₃ 3-CN-Phenyl 83 cyclopropyl 3-CN-Phenyl 84 Cyclobutyl 3-CN-Phenyl 85 cyclopentyl 3-CN-Phenyl 86 cyclohexyl 3-CN-Phenyl 87 3-pyridyl 3-CN-Phenyl 88 1-methyl-1H- 3-CN-Phenyl pyrazol-4-yl 89 1H-imidazol-4-yl 3-CN-Phenyl 90 2-furanyl 3-CN-Phenyl 91 ethyl 2-F-Phenyl 92 n-propyl 2-F-Phenyl 93 isopropyl 2-F-Phenyl 94 —CH₂CH(CH₃)₂ 2-F-Phenyl 95 —CF₃ 2-F-Phenyl 96 —CH₂CF₃ 2-F-Phenyl 97 —CH₂CH₂CF₃ 2-F-Phenyl 98 cyclopropyl 2-F-Phenyl 99 Cyclobutyl 2-F-Phenyl 100 cyclopentyl 2-F-Phenyl 101 cyclohexyl 2-F-Phenyl 102 3-pyridyl 2-F-Phenyl 103 1-methyl-1H- 2-F-Phenyl pyrazol-4-yl 104 1H-imidazol-4-yl 2-F-Phenyl 105 2-furanyl 2-F-Phenyl 106 ethyl 4-F-Phenyl 107 n-propyl 4-F-Phenyl 108 isopropyl 4-F-Phenyl 109 —CH₂CH(CH₃)₂ 4-F-Phenyl 110 —CF₃ 4-F-Phenyl 111 —CH₂CF₃ 4-F-Phenyl 112 —CH₂CH₂CF₃ 4-F-Phenyl 113 cyclopropyl 4-F-Phenyl 114 Cyclobutyl 4-F-Phenyl 115 cyclopentyl 4-F-Phenyl 116 cyclohexyl 4-F-Phenyl 117 3-pyridyl 4-F-Phenyl 118 1-methyl-1H- 4-F-Phenyl pyrazol-4-yl 119 1H-imidazol-4-yl 4-F-Phenyl 120 2-furanyl 4-F-Phenyl 121 ethyl 3-Cl-Phenyl 122 n-propyl 3-Cl-Phenyl 123 isopropyl 3-Cl-Phenyl 124 —CH₂CH(CH₃)₂ 3-Cl-Phenyl 125 —CF₃ 3-Cl-Phenyl 126 —CH₂CF₃ 3-Cl-Phenyl 127 —CH₂CH₂CF₃ 3-Cl-Phenyl 128 cyclopropyl 3-Cl-Phenyl 129 Cyclobutyl 3-Cl-Phenyl 130 cyclopentyl 3-Cl-Phenyl 131 cyclohexyl 3-Cl-Phenyl 132 3-pyridyl 3-Cl-Phenyl 133 1-methyl-1H- 3-Cl-Phenyl pyrazol-4-yl 134 1H-imidazol-4-yl 3-Cl-Phenyl 135 2-furanyl 3-Cl-Phenyl 136 ethyl 2-Br-Phenyl 137 n-propyl 2-Br-Phenyl 138 isopropyl 2-Br-Phenyl 139 —CH₂CH(CH₃)₂ 2-Br-Phenyl 140 —CF₃ 2-Br-Phenyl 141 —CH₂CF₃ 2-Br-Phenyl 142 —CH₂CH₂CF₃ 2-Br-Phenyl 143 cyclopropyl 2-Br-Phenyl 144 Cyclobutyl 2-Br-Phenyl 145 cyclopentyl 2-Br-Phenyl 146 cyclohexyl 2-Br-Phenyl 147 3-pyridyl 2-Br-Phenyl 148 1-methyl-1H- 2-Br-Phenyl pyrazol-4-yl 149 1H-imidazol-4-yl 2-Br-Phenyl 150 2-furanyl 2-Br-Phenyl 151 ethyl 4-Br-Phenyl 152 n-propyl 4-Br-Phenyl 153 isopropyl 4-Br-Phenyl 154 —CH₂CH(CH₃)₂ 4-Br-Phenyl 155 —CF₃ 4-Br-Phenyl 156 —CH₂CF₃ 4-Br-Phenyl 157 —CH₂CH₂CF₃ 4-Br-Phenyl 158 cyclopropyl 4-Br-Phenyl 159 Cyclobutyl 4-Br-Phenyl 160 cyclopentyl 4-Br-Phenyl 161 cyclohexyl 4-Br-Phenyl 162 3-pyridyl 4-Br-Phenyl 163 1-methyl-1H- 4-Br-Phenyl pyrazol-4-yl 164 1H-imidazol-4-yl 4-Br-Phenyl 165 2-furanyl 4-Br-Phenyl 166 ethyl 3-CF₃-Phenyl 167 n-propyl 3-CF₃-Phenyl 168 isopropyl 3-CF₃-Phenyl 169 —CH₂CH(CH₃)₂ 3-CF₃-Phenyl 170 —CF₃ 3-CF₃-Phenyl 171 —CH₂CF₃ 3-CF₃-Phenyl 172 —CH₂CH₂CF₃ 3-CF₃-Phenyl 173 cyclopropyl 3-CF₃-Phenyl 174 Cyclobutyl 3-CF₃-Phenyl 175 cyclopentyl 3-CF₃-Phenyl 176 cyclohexyl 3-CF₃-Phenyl 177 3-pyridyl 3-CF₃-Phenyl 178 1-methyl-1H- 3-CF₃-Phenyl pyrazol-4-yl 179 1H-imidazol-4-yl 3-CF₃-Phenyl 180 2-furanyl 3-CF₃-Phenyl 181 ethyl 2-iPr-Phenyl 182 n-propyl 2-iPr-Phenyl 183 isopropyl 2-iPr-Phenyl 184 —CH₂CH(CH₃)₂ 2-iPr-Phenyl 185 —CF₃ 2-iPr-Phenyl 186 —CH₂CF₃ 2-iPr-Phenyl 187 —CH₂CH₂CF₃ 2-iPr-Phenyl 188 cyclopropyl 2-iPr-Phenyl 189 Cyclobutyl 2-iPr-Phenyl 190 cyclopentyl 2-iPr-Phenyl 191 cyclohexyl 2-iPr-Phenyl 192 3-pyridyl 2-iPr-Phenyl 193 1-methyl-1H- 2-iPr-Phenyl pyrazol-4-yl 194 1H-imidazol-4-yl 2-iPr-Phenyl 195 2-furanyl 2-iPr-Phenyl 196 ethyl 4-iPr-Phenyl 197 n-propyl 4-iPr-Phenyl 198 isopropyl 4-iPr-Phenyl 199 —CH₂CH(CH₃)₂ 4-iPr-Phenyl 200 —CF₃ 4-iPr-Phenyl 201 —CH₂CF₃ 4-iPr-Phenyl 202 —CH₂CH₂CF₃ 4-iPr-Phenyl 203 cyclopropyl 4-iPr-Phenyl 204 Cyclobutyl 4-iPr-Phenyl 205 cyclopentyl 4-iPr-Phenyl 206 cyclohexyl 4-iPr-Phenyl 207 3-pyridyl 4-iPr-Phenyl 208 1-methyl-1H- 4-iPr-Phenyl pyrazol-4-yl 209 1H-imidazol-4-yl 4-iPr-Phenyl 210 2-furanyl 4-iPr-Phenyl 211 ethyl 3-morpholino-phenyl 212 n-propyl 3-morpholino-phenyl 213 isopropyl 3-morpholino-phenyl 214 —CH₂CH(CH₃)₂ 3-morpholino-phenyl 215 —CF₃ 3-morpholino-phenyl 216 —CH₂CF₃ 3-morpholino-phenyl 217 —CH₂CH₂CF₃ 3-morpholino-phenyl 218 cyclopropyl 3-morpholino-phenyl 219 Cyclobutyl 3-morpholino-phenyl 220 cyclopentyl 3-morpholino-phenyl 221 cyclohexyl 3-morpholino-phenyl 222 3-pyridyl 3-morpholino-phenyl 223 1-methyl-1H- 3-morpholino-phenyl pyrazol-4-yl 224 1H-imidazol-4-yl 3-morpholino-phenyl 225 2-furanyl 3-morpholino-phenyl 226 ethyl 4-cyano-2-morpholino- phenyl 227 n-propyl 4-cyano-2-morpholino- phenyl 228 isopropyl 4-cyano-2-morpholino- phenyl 229 —CH₂CH(CH₃)₂ 4-cyano-2-morpholino- phenyl 230 —CF₃ 4-cyano-2-morpholino- phenyl 231 —CH₂CF₃ 4-cyano-2-morpholino- phenyl 232 —CH₂CH₂CF₃ 4-cyano-2-morpholino- phenyl 233 cyclopropyl 4-cyano-2-morpholino- phenyl 234 Cyclobutyl 4-cyano-2-morpholino- phenyl 235 cyclopentyl 4-cyano-2-morpholino- phenyl 236 cyclohexyl 4-cyano-2-morpholino- phenyl 237 3-pyridyl 4-cyano-2-morpholino- phenyl 238 1-methyl-1H- 4-cyano-2-morpholino- pyrazol-4-yl phenyl 239 1H-imidazol-4-yl 4-cyano-2-morpholino- phenyl 240 2-furanyl 4-cyano-2-morpholino- phenyl 241 ethyl 4-hydroxy-2- morpholino-phenyl 242 n-propyl 4-hydroxy-2- morpholino-phenyl 243 isopropyl 4-hydroxy-2- morpholino-phenyl 244 —CH₂CH(CH₃)₂ 4-hydroxy-2- morpholino-phenyl 245 —CF₃ 4-hydroxy-2- morpholino-phenyl 246 —CH₂CF₃ 4-hydroxy-2- morpholino-phenyl 247 —CH₂CH₂CF₃ 4-hydroxy-2- morpholino-phenyl 248 cyclopropyl 4-hydroxy-2- morpholino-phenyl 249 Cyclobutyl 4-hydroxy-2- morpholino-phenyl 250 cyclopentyl 4-hydroxy-2- morpholino-phenyl 251 cyclohexyl 4-hydroxy-2- morpholino-phenyl 252 3-pyridyl 4-hydroxy-2- morpholino-phenyl 253 1-methyl-1H- 4-hydroxy-2- pyrazol-4-yl morpholino-phenyl 254 1H-imidazol-4-yl 4-hydroxy-2- morpholino-phenyl 255 2-furanyl 4-hydroxy-2- morpholino-phenyl 256 ethyl 2-CH₃-phenyl 257 n-propyl 2-CH₃-phenyl 258 isopropyl 2-CH₃-phenyl 259 —CH₂CH(CH₃)₂ 2-CH₃-phenyl 260 CF₃ 2-CH₃-phenyl 261 —CH₂ CF₃ 2-CH₃-phenyl 262 —CH₂CH₂CF₃ 2-CH₃-phenyl 263 cyclopropyl 2-CH₃-phenyl 264 Cyclobutyl 2-CH₃-phenyl 265 cyclopentyl 2-CH₃-phenyl 266 cyclohexyl 2-CH₃-phenyl 267 3-pyridyl 2-CH₃-phenyl 268 1-methyl-1H- 2-CH₃-phenyl pyrazol-4-yl 269 1H-imidazol-4-yl 2-CH₃-phenyl 270 2-furanyl 2-CH₃-phenyl 271 ethyl 4-OH-Phenyl 272 n-propyl 4-OH-Phenyl 273 isopropyl 4-OH-Phenyl 274 —CH₂CH(CH₃)₂ 4-OH-Phenyl 275 —CF₃ 4-OH-Phenyl 276 —CH₂CF₃ 4-OH-Phenyl 277 —CH₂CH₂CF₃ 4-OH-Phenyl 278 cyclopropyl 4-OH-Phenyl 279 Cyclobutyl 4-OH-Phenyl 280 cyclopentyl 4-OH-Phenyl 281 cyclohexyl 4-OH-Phenyl 282 3-pyridyl 4-OH-Phenyl 283 1-methyl-1H- 4-OH-Phenyl pyrazol-4-yl 284 1H-imidazol-4-yl 4-OH-Phenyl 285 2-furanyl 4-OH-Phenyl 286 ethyl 2-OH-Phenyl 287 n-propyl 2-OH-Phenyl 288 isopropyl 2-OH-Phenyl 289 —CH₂CH(CH₃)₂ 2-OH-Phenyl 290 —CF₃ 2-OH-Phenyl 291 —CH₂CF₃ 2-OH-Phenyl 292 —CH₂CH₂CF₃ 2-OH-Phenyl 293 cyclopropyl 2-OH-Phenyl 294 Cyclobutyl 2-OH-Phenyl 295 cyclopentyl 2-OH-Phenyl 296 cyclohexyl 2-OH-Phenyl 297 3-pyridyl 2-OH-Phenyl 298 1-methyl-1H- 2-OH-Phenyl pyrazol-4-yl 299 1H-imidazol-4-yl 2-OH-Phenyl 300 2-furanyl 2-OH-Phenyl 301 ethyl 3-OMe-Phenyl 302 n-propyl 3-OMe-Phenyl 303 isopropyl 3-OMe-Phenyl 304 —CH₂CH(CH₃)₂ 3-OMe-Phenyl 305 —CF₃ 3-OMe-Phenyl 306 —CH₂CF₃ 3-OMe-Phenyl 307 —CH₂CH₂CF₃ 3-OMe-Phenyl 308 cyclopropyl 3-OMe-Phenyl 309 Cyclobutyl 3-OMe-Phenyl 310 cyclopentyl 3-OMe-Phenyl 311 cyclohexyl 3-OMe-Phenyl 312 3-pyridyl 3-OMe-Phenyl 313 1-methyl-1H- 3-OMe-Phenyl pyrazol-4-yl 314 1H-imidazol-4-yl 3-OMe-Phenyl 315 2-furanyl 3-OMe-Phenyl 316 ethyl 4-CN-Phenyl 317 n-propyl 4-CN-Phenyl 318 isopropyl 4-CN-Phenyl 319 —CH₂CH(CH₃)₂ 4-CN-Phenyl 320 —CF₃ 4-CN-Phenyl 321 —CH₂CF₃ 4-CN-Phenyl 322 —CH₂CH₂CF₃ 4-CN-Phenyl 323 cyclopropyl 4-CN-Phenyl 324 Cyclobutyl 4-CN-Phenyl 325 cyclopentyl 4-CN-Phenyl 326 cyclohexyl 4-CN-Phenyl 327 3-pyridyl 4-CN-Phenyl 328 1-methyl-1H- 4-CN-Phenyl pyrazol-4-yl 329 1H-imidazol-4-yl 4-CN-Phenyl 330 2-furanyl 4-CN-Phenyl 331 ethyl 2-CN-Phenyl 332 n-propyl 2-CN-Phenyl 333 isopropyl 2-CN-Phenyl 334 —CH₂CH(CH₃)₂ 2-CN-Phenyl 335 —CF₃ 2-CN-Phenyl 336 —CH₂CF₃ 2-CN-Phenyl 337 —CH₂CH₂CF₃ 2-CN-Phenyl 338 cyclopropyl 2-CN-Phenyl 339 Cyclobutyl 2-CN-Phenyl 340 cyclopentyl 2-CN-Phenyl 341 cyclohexyl 2-CN-Phenyl 342 3-pyridyl 2-CN-Phenyl 343 1-methyl-1H- 2-CN-Phenyl pyrazol-4-yl 344 1H-imidazol-4-yl 2-CN-Phenyl 345 2-furanyl 2-CN-Phenyl 346 ethyl 3-F-Phenyl 347 n-propyl 3-F-Phenyl 348 isopropyl 3-F-Phenyl 349 —CH₂CH(CH₃)₂ 3-F-Phenyl 350 —CF₃ 3-F-Phenyl 351 —CH₂CF₃ 3-F-Phenyl 352 —CH₂CH₂CF₃ 3-F-Phenyl 353 cyclopropyl 3-F-Phenyl 354 Cyclobutyl 3-F-Phenyl 355 cyclopentyl 3-F-Phenyl 356 cyclohexyl 3-F-Phenyl 357 3-pyridyl 3-F-Phenyl 358 1-methyl-1H- 3-F-Phenyl pyrazol-4-yl 359 1H-imidazol-4-yl 3-F-Phenyl 360 2-furanyl 3-F-Phenyl 361 ethyl 2-Cl-Phenyl 362 n-propyl 2-Cl-Phenyl 363 isopropyl 2-Cl-Phenyl 364 —CH₂CH(CH₃)₂ 2-Cl-Phenyl 365 —CF₃ 2-Cl-Phenyl 366 —CH₂CF₃ 2-Cl-Phenyl 367 —CH₂CH₂CF₃ 2-Cl-Phenyl 368 cyclopropyl 2-Cl-Phenyl 369 Cyclobutyl 2-Cl-Phenyl 370 cyclopentyl 2-Cl-Phenyl 371 cyclohexyl 2-Cl-Phenyl 372 3-pyridyl 2-Cl-Phenyl 373 1-methyl-1H- 2-Cl-Phenyl pyrazol-4-yl 374 1H-imidazol-4-yl 2-Cl-Phenyl 375 2-furanyl 2-Cl-Phenyl 376 ethyl 4-Cl-Phenyl 377 n-propyl 4-Cl-Phenyl 378 isopropyl 4-Cl-Phenyl 379 —CH₂CH(CH₃)₂ 4-Cl-Phenyl 380 —CF₃ 4-Cl-Phenyl 381 —CH₂CF₃ 4-Cl-Phenyl 382 —CH₂CH₂CF₃ 4-Cl-Phenyl 383 cyclopropyl 4-Cl-Phenyl 384 Cyclobutyl 4-Cl-Phenyl 385 cyclopentyl 4-Cl-Phenyl 386 cyclohexyl 4-Cl-Phenyl 387 3-pyridyl 4-Cl-Phenyl 388 1-methyl-1H- 4-Cl-Phenyl pyrazol-4-yl 389 1H-imidazol-4-yl 4-Cl-Phenyl 390 2-furanyl 4-Cl-Phenyl 391 ethyl 3-Br-Phenyl 392 n-propyl 3-Br-Phenyl 393 isopropyl 3-Br-Phenyl 394 —CH₂CH(CH₃)₂ 3-Br-Phenyl 395 —CF₃ 3-Br-Phenyl 396 —CH₂CF₃ 3-Br-Phenyl 397 —CH₂CH₂CF₃ 3-Br-Phenyl 398 cyclopropyl 3-Br-Phenyl 399 Cyclobutyl 3-Br-Phenyl 400 cyclopentyl 3-Br-Phenyl 401 cyclohexyl 3-Br-Phenyl 402 3-pyridyl 3-Br-Phenyl 403 1-methyl-1H- 3-Br-Phenyl pyrazol-4-yl 404 1H-imidazol-4-yl 3-Br-Phenyl 405 2-furanyl 3-Br-Phenyl 406 ethyl 2-CF₃-Phenyl 407 n-propyl 2-CF₃-Phenyl 408 isopropyl 2-CF₃-Phenyl 409 —CH₂CH(CH₃)₂ 2-CF₃-Phenyl 410 —CF₃ 2-CF₃-Phenyl 411 —CH₂CF₃ 2-CF₃-Phenyl 412 —CH₂CH₂CF₃ 2-CF₃-Phenyl 413 cyclopropyl 2-CF₃-Phenyl 414 Cyclobutyl 2-CF₃-Phenyl 415 cyclopentyl 2-CF₃-Phenyl 416 cyclohexyl 2-CF₃-Phenyl 417 3-pyridyl 2-CF₃-Phenyl 418 1-methyl-1H- 2-CF₃-Phenyl pyrazol-4-yl 419 1H-imidazol-4-yl 2-CF₃-Phenyl 420 2-furanyl 2-CF₃-Phenyl 421 ethyl 4-CF₃-Phenyl 422 n-propyl 4-CF₃-Phenyl 423 isopropyl 4-CF₃-Phenyl 424 —CH₂CH(CH₃)₂ 4-CF₃-Phenyl 425 —CF₃ 4-CF₃-Phenyl 426 —CH₂CF₃ 4-CF₃-Phenyl 427 —CH₂CH₂CF₃ 4-CF₃-Phenyl 428 cyclopropyl 4-CF₃-Phenyl 429 Cyclobutyl 4-CF₃-Phenyl 430 cyclopentyl 4-CF₃-Phenyl 431 cyclohexyl 4-CF₃-Phenyl 432 3-pyridyl 4-CF₃-Phenyl 433 1-methyl-1H- 4-CF₃-Phenyl pyrazol-4-yl 434 1H-imidazol-4-yl 4-CF₃-Phenyl 435 2-furanyl 4-CF₃-Phenyl 436 ethyl 3-iPr-Phenyl 437 n-propyl 3-iPr-Phenyl 438 isopropyl 3-iPr-Phenyl 439 —CH₂CH(CH₃)₂ 3-iPr-Phenyl 440 —CF₃ 3-iPr-Phenyl 441 —CH₂CF₃ 3-iPr-Phenyl 442 —CH₂CH₂CF₃ 3-iPr-Phenyl 443 cyclopropyl 3-iPr-Phenyl 444 Cyclobutyl 3-iPr-Phenyl 445 cyclopentyl 3-iPr-Phenyl 446 cyclohexyl 3-iPr-Phenyl 447 3-pyridyl 3-iPr-Phenyl 448 1-methyl-1H- 3-iPr-Phenyl pyrazol-4-yl 449 1H-imidazol-4-yl 3-iPr-Phenyl 450 2-furanyl 3-iPr-Phenyl 451 ethyl 2-morpholino- phenyl 452 n-propyl 2-morpholino- phenyl 453 isopropyl 2-morpholino- phenyl 454 —CH₂CH(CH₃)₂ 2-morpholino- phenyl 455 —CF₃ 2-morpholino- phenyl 456 —CH₂CF₃ 2-morpholino- phenyl 457 —CH₂CH₂CF₃ 2-morpholino- phenyl 458 cyclopropyl 2-morpholino- phenyl 459 Cyclobutyl 2-morpholino- phenyl 460 cyclopentyl 2-morpholino- phenyl 461 cyclohexyl 2-morpholino- phenyl 462 3-pyridyl 2-morpholino- phenyl 463 1-methyl-1H- 2-morpholino- pyrazol-4-yl phenyl 464 1H-imidazol-4-yl 2-morpholino- phenyl 465 2-furanyl 2-morpholino- phenyl 466 ethyl 4-morpholino- phenyl 467 n-propyl 4-morpholino- phenyl 468 isopropyl 4-morpholino- phenyl 469 —CH₂CH(CH₃)₂ 4-morpholino- phenyl 470 —CF₃ 4-morpholino- phenyl 471 —CH₂CF₃ 4-morpholino- phenyl 472 —CH₂CH₂CF₃ 4-morpholino- phenyl 473 cyclopropyl 4-morpholino- phenyl 474 Cyclobutyl 4-morpholino- phenyl 475 cyclopentyl 4-morpholino- phenyl 476 cyclohexyl 4-morpholino- phenyl 477 3-pyridyl 4-morpholino- phenyl 478 1-methyl-1H- 4-morpholino- pyrazol-4-yl phenyl 479 1H-imidazol-4-yl 4-morpholino- phenyl 480 2-furanyl 4-morpholino- phenyl 481 ethyl 4-methyl-2- morpholino-phenyl 482 n-propyl 4-methyl-2- morpholino-phenyl 483 isopropyl 4-methyl-2- morpholino-phenyl 484 —CH₂CH(CH₃)₂ 4-methyl-2- morpholino-phenyl 485 —CF₃ 4-methyl-2- morpholino-phenyl 486 —CH₂CF₃ 4-methyl-2- morpholino-phenyl 487 —CH₂CH₂CF₃ 4-methyl-2- morpholino-phenyl 488 cyclopropyl 4-methyl-2- morpholino-phenyl 489 Cyclobutyl 4-methyl-2- morpholino-phenyl 490 cyclopentyl 4-methyl-2- morpholino-phenyl 491 cyclohexyl 4-methyl-2- morpholino-phenyl 492 3-pyridyl 4-methyl-2- morpholino-phenyl 493 1-methyl-1H- 4-methyl-2- pyrazol-4-yl morpholino-phenyl 494 1H-imidazol-4-yl 4-methyl-2- morpholino-phenyl 495 2-furanyl 4-methyl-2- morpholino-phenyl

Exemplary embodiments include compounds having the formula (XXVI)

or a pharmaceutically acceptable salt form thereof defined herein below in Table 10.

TABLE 10 Entry R^(2d) R³ 1 ethyl 4-CH₃-phenyl 2 n-propyl 4-CH₃-phenyl 3 isopropyl 4-CH₃-phenyl 4 —CH₂CH(CH₃)₂ 4-CH₃-phenyl 5 CF₃ 4-CH₃-phenyl 6 —CH₂ CF₃ 4-CH₃-phenyl 7 —CH₂CH₂CF₃ 4-CH₃-phenyl 8 cyclopropyl 4-CH₃-phenyl 9 Cyclobutyl 4-CH₃-phenyl 10 cyclopentyl 4-CH₃-phenyl 11 cyclohexyl 4-CH₃-phenyl 12 3-pyridyl 4-CH₃-phenyl 13 1-methyl-1H- 4-CH₃-phenyl pyrazol-4-yl 14 1H-imidazol-4-yl 4-CH₃-phenyl 15 2-furanyl 4-CH₃-phenyl 16 ethyl 3-CH₃-phenyl 17 n-propyl 3-CH₃-phenyl 18 isopropyl 3-CH₃-phenyl 19 —CH₂CH(CH₃)₂ 3-CH₃-phenyl 20 —CF₃ 3-CH₃-phenyl 21 —CH₂CF₃ 3-CH₃-phenyl 22 —CH₂CH₂CF₃ 3-CH₃-phenyl 23 cyclopropyl 3-CH₃-phenyl 24 Cyclobutyl 3-CH₃-phenyl 25 cyclopentyl 3-CH₃-phenyl 26 cyclohexyl 3-CH₃-phenyl 27 3-pyridyl 3-CH₃-phenyl 28 1-methyl-1H- 3-CH₃-phenyl pyrazol-4-yl 29 1H-imidazol-4-yl 3-CH₃-phenyl 30 2-furanyl 3-CH₃-phenyl 31 ethyl 3-OH-Phenyl 32 n-propyl 3-OH-Phenyl 33 isopropyl 3-OH-Phenyl 34 —CH₂CH(CH₃)₂ 3-OH-Phenyl 35 —CF₃ 3-OH-Phenyl 36 —CH₂CF₃ 3-OH-Phenyl 37 —CH₂CH₂CF₃ 3-OH-Phenyl 38 cyclopropyl 3-OH-Phenyl 39 Cyclobutyl 3-OH-Phenyl 40 cyclopentyl 3-OH-Phenyl 41 cyclohexyl 3-OH-Phenyl 42 3-pyridyl 3-OH-Phenyl 43 1-methyl-1H- 3-OH-Phenyl pyrazol-4-yl 44 1H-imidazol-4-yl 3-OH-Phenyl 45 2-furanyl 3-OH-Phenyl 46 ethyl 4-OMe-Phenyl 47 n-propyl 4-OMe-Phenyl 48 isopropyl 4-OMe-Phenyl 49 —CH₂CH(CH₃)₂ 4-OMe-Phenyl 50 —CF₃ 4-OMe-Phenyl 51 —CH₂CF₃ 4-OMe-Phenyl 52 —CH₂CH₂CF₃ 4-OMe-Phenyl 53 cyclopropyl 4-OMe-Phenyl 54 Cyclobutyl 4-OMe-Phenyl 55 cyclopentyl 4-OMe-Phenyl 56 cyclohexyl 4-OMe-Phenyl 57 3-pyridyl 4-OMe-Phenyl 58 1-methyl-1H- 4-OMe-Phenyl pyrazol-4-yl 59 1H-imidazol-4-yl 4-OMe-Phenyl 60 2-furanyl 4-OMe-Phenyl 61 ethyl 2-OMe-Phenyl 62 n-propyl 2-OMe-Phenyl 63 isopropyl 2-OMe-Phenyl 64 —CH₂CH(CH₃)₂ 2-OMe-Phenyl 65 —CF₃ 2-OMe-Phenyl 66 —CH₂CF₃ 2-OMe-Phenyl 67 —CH₂CH₂CF₃ 2-OMe-Phenyl 68 cyclopropyl 2-OMe-Phenyl 69 Cyclobutyl 2-OMe-Phenyl 70 cyclopentyl 2-OMe-Phenyl 71 cyclohexyl 2-OMe-Phenyl 72 3-pyridyl 2-OMe-Phenyl 73 1-methyl-1H- 2-OMe-Phenyl pyrazol-4-yl 74 1H-imidazol-4-yl 2-OMe-Phenyl 75 2-furanyl 2-OMe-Phenyl 76 ethyl 3-CN-Phenyl 77 n-propyl 3-CN-Phenyl 78 isopropyl 3-CN-Phenyl 79 —CH₂CH(CH₃)₂ 3-CN-Phenyl 80 —CF₃ 3-CN-Phenyl 81 —CH₂CF₃ 3-CN-Phenyl 82 —CH₂CH₂CF₃ 3-CN-Phenyl 83 cyclopropyl 3-CN-Phenyl 84 Cyclobutyl 3-CN-Phenyl 85 cyclopentyl 3-CN-Phenyl 86 cyclohexyl 3-CN-Phenyl 87 3-pyridyl 3-CN-Phenyl 88 1-methyl-1H- 3-CN-Phenyl pyrazol-4-yl 89 1H-imidazol-4-yl 3-CN-Phenyl 90 2-furanyl 3-CN-Phenyl 91 ethyl 2-F-Phenyl 92 n-propyl 2-F-Phenyl 93 isopropyl 2-F-Phenyl 94 —CH₂CH(CH₃)₂ 2-F-Phenyl 95 —CF₃ 2-F-Phenyl 96 —CH₂CF₃ 2-F-Phenyl 97 —CH₂CH₂CF₃ 2-F-Phenyl 98 cyclopropyl 2-F-Phenyl 99 Cyclobutyl 2-F-Phenyl 100 cyclopentyl 2-F-Phenyl 101 cyclohexyl 2-F-Phenyl 102 3-pyridyl 2-F-Phenyl 103 1-methyl-1H- 2-F-Phenyl pyrazol-4-yl 104 1H-imidazol-4-yl 2-F-Phenyl 105 2-furanyl 2-F-Phenyl 106 ethyl 4-F-Phenyl 107 n-propyl 4-F-Phenyl 108 isopropyl 4-F-Phenyl 109 —CH₂CH(CH₃)₂ 4-F-Phenyl 110 —CF₃ 4-F-Phenyl 111 —CH₂CF₃ 4-F-Phenyl 112 —CH₂CH₂CF₃ 4-F-Phenyl 113 cyclopropyl 4-F-Phenyl 114 Cyclobutyl 4-F-Phenyl 115 cyclopentyl 4-F-Phenyl 116 cyclohexyl 4-F-Phenyl 117 3-pyridyl 4-F-Phenyl 118 1-methyl-1H- 4-F-Phenyl pyrazol-4-yl 119 1H-imidazol-4-yl 4-F-Phenyl 120 2-furanyl 4-F-Phenyl 121 ethyl 3-Cl-Phenyl 122 n-propyl 3-Cl-Phenyl 123 isopropyl 3-Cl-Phenyl 124 —CH₂CH(CH₃)₂ 3-Cl-Phenyl 125 —CF₃ 3-Cl-Phenyl 126 —CH₂CF₃ 3-Cl-Phenyl 127 —CH₂CH₂CF₃ 3-Cl-Phenyl 128 cyclopropyl 3-Cl-Phenyl 129 Cyclobutyl 3-Cl-Phenyl 130 cyclopentyl 3-Cl-Phenyl 131 cyclohexyl 3-Cl-Phenyl 132 3-pyridyl 3-Cl-Phenyl 133 1-methyl-1H- 3-Cl-Phenyl pyrazol-4-yl 134 1H-imidazol-4-yl 3-Cl-Phenyl 135 2-furanyl 3-Cl-Phenyl 136 ethyl 2-Br-Phenyl 137 n-propyl 2-Br-Phenyl 138 isopropyl 2-Br-Phenyl 139 —CH₂CH(CH₃)₂ 2-Br-Phenyl 140 —CF₃ 2-Br-Phenyl 141 —CH₂CF₃ 2-Br-Phenyl 142 —CH₂CH₂CF₃ 2-Br-Phenyl 143 cyclopropyl 2-Br-Phenyl 144 Cyclobutyl 2-Br-Phenyl 145 cyclopentyl 2-Br-Phenyl 146 cyclohexyl 2-Br-Phenyl 147 3-pyridyl 2-Br-Phenyl 148 1-methyl-1H- 2-Br-Phenyl pyrazol-4-yl 149 1H-imidazol-4-yl 2-Br-Phenyl 150 2-furanyl 2-Br-Phenyl 151 ethyl 4-Br-Phenyl 152 n-propyl 4-Br-Phenyl 153 isopropyl 4-Br-Phenyl 154 —CH₂CH(CH₃)₂ 4-Br-Phenyl 155 —CF₃ 4-Br-Phenyl 156 —CH₂CF₃ 4-Br-Phenyl 157 —CH₂CH₂CF₃ 4-Br-Phenyl 158 cyclopropyl 4-Br-Phenyl 159 Cyclobutyl 4-Br-Phenyl 160 cyclopentyl 4-Br-Phenyl 161 cyclohexyl 4-Br-Phenyl 162 3-pyridyl 4-Br-Phenyl 163 1-methyl-1H- 4-Br-Phenyl pyrazol-4-yl 164 1H-imidazol-4-yl 4-Br-Phenyl 165 2-furanyl 4-Br-Phenyl 166 ethyl 3-CF₃-Phenyl 167 n-propyl 3-CF₃-Phenyl 168 isopropyl 3-CF₃-Phenyl 169 —CH₂CH(CH₃)₂ 3-CF₃-Phenyl 170 —CF₃ 3-CF₃-Phenyl 171 —CH₂CF₃ 3-CF₃-Phenyl 172 —CH₂CH₂CF₃ 3-CF₃-Phenyl 173 cyclopropyl 3-CF₃-Phenyl 174 Cyclobutyl 3-CF₃-Phenyl 175 cyclopentyl 3-CF₃-Phenyl 176 cyclohexyl 3-CF₃-Phenyl 177 3-pyridyl 3-CF₃-Phenyl 178 1-methyl-1H- 3-CF₃-Phenyl pyrazol-4-yl 179 1H-imidazol-4-yl 3-CF₃-Phenyl 180 2-furanyl 3-CF₃-Phenyl 181 ethyl 2-iPr-Phenyl 182 n-propyl 2-iPr-Phenyl 183 isopropyl 2-iPr-Phenyl 184 —CH₂CH(CH₃)₂ 2-iPr-Phenyl 185 —CF₃ 2-iPr-Phenyl 186 —CH₂CF₃ 2-iPr-Phenyl 187 —CH₂CH₂CF₃ 2-iPr-Phenyl 188 cyclopropyl 2-iPr-Phenyl 189 Cyclobutyl 2-iPr-Phenyl 190 cyclopentyl 2-iPr-Phenyl 191 cyclohexyl 2-iPr-Phenyl 192 3-pyridyl 2-iPr-Phenyl 193 1-methyl-1H- 2-iPr-Phenyl pyrazol-4-yl 194 1H-imidazol-4-yl 2-iPr-Phenyl 195 2-furanyl 2-iPr-Phenyl 196 ethyl 4-iPr-Phenyl 197 n-propyl 4-iPr-Phenyl 198 isopropyl 4-iPr-Phenyl 199 —CH₂CH(CH₃)₂ 4-iPr-Phenyl 200 —CF₃ 4-iPr-Phenyl 201 —CH₂CF₃ 4-iPr-Phenyl 202 —CH₂CH₂CF₃ 4-iPr-Phenyl 203 cyclopropyl 4-iPr-Phenyl 204 Cyclobutyl 4-iPr-Phenyl 205 cyclopentyl 4-iPr-Phenyl 206 cyclohexyl 4-iPr-Phenyl 207 3-pyridyl 4-iPr-Phenyl 208 1-methyl-1H- 4-iPr-Phenyl pyrazol-4-yl 209 1H-imidazol-4-yl 4-iPr-Phenyl 210 2-furanyl 4-iPr-Phenyl 211 ethyl 3-morpholino- phenyl 212 n-propyl 3-morpholino- phenyl 213 isopropyl 3-morpholino- phenyl 214 —CH₂CH(CH₃)₂ 3-morpholino- phenyl 215 —CF₃ 3-morpholino- phenyl 216 —CH₂CF₃ 3-morpholino- phenyl 217 —CH₂CH₂CF₃ 3-morpholino- phenyl 218 cyclopropyl 3-morpholino- phenyl 219 Cyclobutyl 3-morpholino- phenyl 220 cyclopentyl 3-morpholino- phenyl 221 cyclohexyl 3-morpholino- phenyl 222 3-pyridyl 3-morpholino- phenyl 223 1-methyl-1H- 3-morpholino- pyrazol-4-yl phenyl 224 1H-imidazol-4-yl 3-morpholino- phenyl 225 2-furanyl 3-morpholino- phenyl 226 ethyl 4-cyano-2- morpholino-phenyl 227 n-propyl 4-cyano-2- morpholino-phenyl 228 isopropyl 4-cyano-2- morpholino-phenyl 229 —CH₂CH(CH₃)₂ 4-cyano-2- morpholino-phenyl 230 —CF₃ 4-cyano-2- morpholino-phenyl 231 —CH₂CF₃ 4-cyano-2- morpholino-phenyl 232 —CH₂CH₂CF₃ 4-cyano-2- morpholino-phenyl 233 cyclopropyl 4-cyano-2- morpholino-phenyl 234 Cyclobutyl 4-cyano-2- morpholino-phenyl 235 cyclopentyl 4-cyano-2- morpholino-phenyl 236 cyclohexyl 4-cyano-2- morpholino-phenyl 237 3-pyridyl 4-cyano-2- morpholino-phenyl 238 1-methyl-1H- 4-cyano-2- pyrazol-4-yl morpholino-phenyl 239 1H-imidazol-4-yl 4-cyano-2- morpholino-phenyl 240 2-furanyl 4-cyano-2- morpholino-phenyl 241 ethyl 4-hydroxy-2- morpholino-phenyl 242 n-propyl 4-hydroxy-2- morpholino-phenyl 243 isopropyl 4-hydroxy-2- morpholino-phenyl 244 —CH₂CH(CH₃)₂ 4-hydroxy-2- morpholino-phenyl 245 —CF₃ 4-hydroxy-2- morpholino-phenyl 246 —CH₂CF₃ 4-hydroxy-2- morpholino-phenyl 247 —CH₂CH₂CF₃ 4-hydroxy-2- morpholino-phenyl 248 cyclopropyl 4-hydroxy-2- morpholino-phenyl 249 Cyclobutyl 4-hydroxy-2- morpholino-phenyl 250 cyclopentyl 4-hydroxy-2- morpholino-phenyl 251 cyclohexyl 4-hydroxy-2- morpholino-phenyl 252 3-pyridyl 4-hydroxy-2- morpholino-phenyl 253 1-methyl-1H- 4-hydroxy-2- pyrazol-4-yl morpholino-phenyl 254 lH-imidazol-4-yl 4-hydroxy-2- morpholino-phenyl 255 2-furanyl 4-hydroxy-2- morpholino-phenyl 256 ethyl 2-CH₃-phenyl 257 n-propyl 2-CH₃-phenyl 258 isopropyl 2-CH₃-phenyl 259 —CH₂CH(CH₃)₂ 2-CH₃-phenyl 260 CF₃ 2-CH₃-phenyl 261 —CH₂ CF₃ 2-CH₃-phenyl 262 —CH₂CH₂CF₃ 2-CH₃-phenyl 263 cyclopropyl 2-CH₃-phenyl 264 Cyclobutyl 2-CH₃-phenyl 265 cyclopentyl 2-CH₃-phenyl 266 cyclohexyl 2-CH₃-phenyl 267 3-pyridyl 2-CH₃-phenyl 268 1-methyl-1H- 2-CH₃-phenyl pyrazol-4-yl 269 lH-imidazol-4-yl 2-CH₃-phenyl 270 2-furanyl 2-CH₃-phenyl 271 ethyl 4-OH-Phenyl 272 n-propyl 4-OH-Phenyl 273 isopropyl 4-OH-Phenyl 274 —CH₂CH(CH₃)₂ 4-OH-Phenyl 275 —CF₃ 4-OH-Phenyl 276 —CH₂CF₃ 4-OH-Phenyl 277 —CH₂CH₂CF₃ 4-OH-Phenyl 278 cyclopropyl 4-OH-Phenyl 279 Cyclobutyl 4-OH-Phenyl 280 cyclopentyl 4-OH-Phenyl 281 cyclohexyl 4-OH-Phenyl 282 3-pyridyl 4-OH-Phenyl 283 1-methyl-1H- 4-OH-Phenyl pyrazol-4-yl 284 1H-imidazol-4-yl 4-OH-Phenyl 285 2-furanyl 4-OH-Phenyl 286 ethyl 2-OH-Phenyl 287 n-propyl 2-OH-Phenyl 288 isopropyl 2-OH-Phenyl 289 —CH₂CH(CH₃)₂ 2-OH-Phenyl 290 —CF₃ 2-OH-Phenyl 291 —CH₂CF₃ 2-OH-Phenyl 292 —CH₂CH₂CF₃ 2-OH-Phenyl 293 cyclopropyl 2-OH-Phenyl 294 Cyclobutyl 2-OH-Phenyl 295 cyclopentyl 2-OH-Phenyl 296 cyclohexyl 2-OH-Phenyl 297 3-pyridyl 2-OH-Phenyl 298 1-methyl-1H- 2-OH-Phenyl pyrazol-4-yl 299 1H-imidazol-4-yl 2-OH-Phenyl 300 2-furanyl 2-OH-Phenyl 301 ethyl 3-OMe-Phenyl 302 n-propyl 3-OMe-Phenyl 303 isopropyl 3-OMe-Phenyl 304 —CH₂CH(CH₃)₂ 3-OMe-Phenyl 305 —CF₃ 3-OMe-Phenyl 306 —CH₂CF₃ 3-OMe-Phenyl 307 —CH₂CH₂CF₃ 3-OMe-Phenyl 308 cyclopropyl 3-OMe-Phenyl 309 Cyclobutyl 3-OMe-Phenyl 310 cyclopentyl 3-OMe-Phenyl 311 cyclohexyl 3-OMe-Phenyl 312 3-pyridyl 3-OMe-Phenyl 313 1-methyl-1H- 3-OMe-Phenyl pyrazol-4-yl 314 1H-imidazol-4-yl 3-OMe-Phenyl 315 2-furanyl 3-OMe-Phenyl 316 ethyl 4-CN-Phenyl 317 n-propyl 4-CN-Phenyl 318 isopropyl 4-CN-Phenyl 319 —CH₂CH(CH₃)₂ 4-CN-Phenyl 320 —CF₃ 4-CN-Phenyl 321 —CH₂CF₃ 4-CN-Phenyl 322 —CH₂CH₂CF₃ 4-CN-Phenyl 323 cyclopropyl 4-CN-Phenyl 324 Cyclobutyl 4-CN-Phenyl 325 cyclopentyl 4-CN-Phenyl 326 cyclohexyl 4-CN-Phenyl 327 3-pyridyl 4-CN-Phenyl 328 1-methyl-1H- 4-CN-Phenyl pyrazol-4-yl 329 1H-imidazol-4-yl 4-CN-Phenyl 330 2-furanyl 4-CN-Phenyl 331 ethyl 2-CN-Phenyl 332 n-propyl 2-CN-Phenyl 333 isopropyl 2-CN-Phenyl 334 —CH₂CH(CH₃)₂ 2-CN-Phenyl 335 —CF₃ 2-CN-Phenyl 336 —CH₂CF₃ 2-CN-Phenyl 337 —CH₂CH₂CF₃ 2-CN-Phenyl 338 cyclopropyl 2-CN-Phenyl 339 Cyclobutyl 2-CN-Phenyl 340 cyclopentyl 2-CN-Phenyl 341 cyclohexyl 2-CN-Phenyl 342 3-pyridyl 2-CN-Phenyl 343 1-methyl-1H- 2-CN-Phenyl pyrazol-4-yl 344 1H-imidazol-4-yl 2-CN-Phenyl 345 2-furanyl 2-CN-Phenyl 346 ethyl 3-F-Phenyl 347 n-propyl 3-F-Phenyl 348 isopropyl 3-F-Phenyl 349 —CH₂CH(CH₃)₂ 3-F-Phenyl 350 —CF₃ 3-F-Phenyl 351 —CH₂CF₃ 3-F-Phenyl 352 —CH₂CH₂CF₃ 3-F-Phenyl 353 cyclopropyl 3-F-Phenyl 354 Cyclobutyl 3-F-Phenyl 355 cyclopentyl 3-F-Phenyl 356 cyclohexyl 3-F-Phenyl 357 3-pyridyl 3-F-Phenyl 358 1-methyl-1H- 3-F-Phenyl pyrazol-4-yl 359 1H-imidazol-4-yl 3-F-Phenyl 360 2-furanyl 3-F-Phenyl 361 ethyl 2-Cl-Phenyl 362 n-propyl 2-Cl-Phenyl 363 isopropyl 2-Cl-Phenyl 364 —CH₂CH(CH₃)₂ 2-Cl-Phenyl 365 —CF₃ 2-Cl-Phenyl 366 —CH₂CF₃ 2-Cl-Phenyl 367 —CH₂CH₂CF₃ 2-Cl-Phenyl 368 cyclopropyl 2-Cl-Phenyl 369 Cyclobutyl 2-Cl-Phenyl 370 cyclopentyl 2-Cl-Phenyl 371 cyclohexyl 2-Cl-Phenyl 372 3-pyridyl 2-Cl-Phenyl 373 1-methyl-1H- 2-Cl-Phenyl pyrazol-4-yl 374 1H-imidazol-4-yl 2-Cl-Phenyl 375 2-furanyl 2-Cl-Phenyl 376 ethyl 4-Cl-Phenyl 377 n-propyl 4-Cl-Phenyl 378 isopropyl 4-Cl-Phenyl 379 —CH₂CH(CH₃)₂ 4-Cl-Phenyl 380 —CF₃ 4-Cl-Phenyl 381 —CH₂CF₃ 4-Cl-Phenyl 382 —CH₂CH₂CF₃ 4-Cl-Phenyl 383 cyclopropyl 4-Cl-Phenyl 384 Cyclobutyl 4-Cl-Phenyl 385 cyclopentyl 4-Cl-Phenyl 386 cyclohexyl 4-Cl-Phenyl 387 3-pyridyl 4-Cl-Phenyl 388 1-methyl-1H- 4-Cl-Phenyl pyrazol-4-yl 389 1H-imidazol-4-yl 4-Cl-Phenyl 390 2-furanyl 4-Cl-Phenyl 391 ethyl 3-Br-Phenyl 392 n-propyl 3-Br-Phenyl 393 isopropyl 3-Br-Phenyl 394 —CH₂CH(CH₃)₂ 3-Br-Phenyl 395 —CF₃ 3-Br-Phenyl 396 —CH₂CF₃ 3-Br-Phenyl 397 —CH₂CH₂CF₃ 3-Br-Phenyl 398 cyclopropyl 3-Br-Phenyl 399 Cyclobutyl 3-Br-Phenyl 400 cyclopentyl 3-Br-Phenyl 401 cyclohexyl 3-Br-Phenyl 402 3-pyridyl 3-Br-Phenyl 403 1-methyl-1H- 3-Br-Phenyl pyrazol-4-yl 404 1H-imidazol-4-yl 3-Br-Phenyl 405 2-furanyl 3-Br-Phenyl 406 ethyl 2-CF₃-Phenyl 407 n-propyl 2-CF₃-Phenyl 408 isopropyl 2-CF₃-Phenyl 409 —CH₂CH(CH₃)₂ 2-CF₃-Phenyl 410 —CF₃ 2-CF₃-Phenyl 411 —CH₂CF₃ 2-CF₃-Phenyl 412 —CH₂CH₂CF₃ 2-CF₃-Phenyl 413 cyclopropyl 2-CF₃-Phenyl 414 Cyclobutyl 2-CF₃-Phenyl 415 cyclopentyl 2-CF₃-Phenyl 416 cyclohexyl 2-CF₃-Phenyl 417 3-pyridyl 2-CF₃-Phenyl 418 1-methyl-1H- 2-CF₃-Phenyl pyrazol-4-yl 419 1H-imidazol-4-yl 2-CF₃-Phenyl 420 2-furanyl 2-CF₃-Phenyl 421 ethyl 4-CF₃-Phenyl 422 n-propyl 4-CF₃-Phenyl 423 isopropyl 4-CF₃-Phenyl 424 —CH₂CH(CH₃)₂ 4-CF₃-Phenyl 425 —CF₃ 4-CF₃-Phenyl 426 —CH₂CF₃ 4-CF₃-Phenyl 427 —CH₂CH₂CF₃ 4-CF₃-Phenyl 428 cyclopropyl 4-CF₃-Phenyl 429 Cyclobutyl 4-CF₃-Phenyl 430 cyclopentyl 4-CF₃-Phenyl 431 cyclohexyl 4-CF₃-Phenyl 432 3-pyridyl 4-CF₃-Phenyl 433 1-methyl-1H- 4-CF₃-Phenyl pyrazol-4-yl 434 1H-imidazol-4-yl 4-CF₃-Phenyl 435 2-furanyl 4-CF₃-Phenyl 436 ethyl 3-iPr-Phenyl 437 n-propyl 3-iPr-Phenyl 438 isopropyl 3-iPr-Phenyl 439 —CH₂CH(CH₃)₂ 3-iPr-Phenyl 440 —CF₃ 3-iPr-Phenyl 441 —CH₂CF₃ 3-iPr-Phenyl 442 —CH₂CH₂CF₃ 3-iPr-Phenyl 443 cyclopropyl 3-iPr-Phenyl 444 Cyclobutyl 3-iPr-Phenyl 445 cyclopentyl 3-iPr-Phenyl 446 cyclohexyl 3-iPr-Phenyl 447 3-pyridyl 3-iPr-Phenyl 448 1-methyl-1H- 3-iPr-Phenyl pyrazol-4-yl 449 1H-imidazol-4-yl 3-iPr-Phenyl 450 2-furanyl 3-iPr-Phenyl 451 ethyl 2-morpholino- phenyl 452 n-propyl 2-morpholino- phenyl 453 isopropyl 2-morpholino- phenyl 454 —CH₂CH(CH₃)₂ 2-morpholino- phenyl 455 —CF₃ 2-morpholino- phenyl 456 —CH₂CF₃ 2-morpholino- phenyl 457 —CH₂CH₂CF₃ 2-morpholino- phenyl 458 cyclopropyl 2-morpholino- phenyl 459 Cyclobutyl 2-morpholino- phenyl 460 cyclopentyl 2-morpholino- phenyl 461 cyclohexyl 2-morpholino- phenyl 462 3-pyridyl 2-morpholino- phenyl 463 1-methyl-1H- 2-morpholino- pyrazol-4-yl phenyl 464 1H-imidazol-4-yl 2-morpholino- phenyl 465 2-furanyl 2-morpholino- phenyl 466 ethyl 4-morpholino- phenyl 467 n-propyl 4-morpholino- phenyl 468 isopropyl 4-morpholino- phenyl 469 —CH₂CH(CH₃)₂ 4-morpholino- phenyl 470 —CF₃ 4-morpholino- phenyl 471 —CH₂CF₃ 4-morpholino- phenyl 472 —CH₂CH₂CF₃ 4-morpholino- phenyl 473 cyclopropyl 4-morpholino- phenyl 474 Cyclobutyl 4-morpholino- phenyl 475 cyclopentyl 4-morpholino- phenyl 476 cyclohexyl 4-morpholino- phenyl 477 3-pyridyl 4-morpholino- phenyl 478 1-methyl-1H- 4-morpholino- pyrazol-4-yl phenyl 479 1H-imidazol-4-yl 4-morpholino- phenyl 480 2-furanyl 4-morpholino- phenyl 481 ethyl 4-methyl-2- morpholino-phenyl 482 n-propyl 4-methyl-2- morpholino-phenyl 483 isopropyl 4-methyl-2- morpholino-phenyl 484 —CH₂CH(CH₃)₂ 4-methyl-2- morpholino-phenyl 485 —CF₃ 4-methyl-2- morpholino-phenyl 486 —CH₂CF₃ 4-methyl-2- morpholino-phenyl 487 —CH₂CH₂CF₃ 4-methyl-2- morpholino-phenyl 488 cyclopropyl 4-methyl-2- morpholino-phenyl 489 Cyclobutyl 4-methyl-2- morpholino-phenyl 490 cyclopentyl 4-methyl-2- morpholino-phenyl 491 cyclohexyl 4-methyl-2- morpholino-phenyl 492 3-pyridyl 4-methyl-2- morpholino-phenyl 493 1-methyl-1H- 4-methyl-2- pyrazol-4-yl morpholino-phenyl 494 1H-imidazol-4-yl 4-methyl-2- morpholino-phenyl 495 2-furanyl 4-methyl-2- morpholino-phenyl

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name 8-(methylsulfonyl)-3-(2-(4-phenylpiperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one.

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name 8-(methylsulfonyl)-3-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one.

For the purposes of the present invention, a compound depicted by the racemic formula, for example:

will stand equally well for either of the two enantiomers having the formula:

or the formula:

or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.

In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. The compounds of the invention may contain any of the substituents, or combinations of substituents, provided herein.

Process for Preparing the 5-hydroxytryptamine receptor 7 Activity Modulators of the Invention

The present invention further relates to a process for preparing the 5-hydroxytryptamine receptor 7 activity modulators of the present invention.

Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein.

The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

The compounds of these teachings can be prepared by methods known in the art of organic chemistry. The reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature. For example, compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes:

General Synthetic Schemes for Preparation of Compounds

The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus may be produced by one of the following reaction schemes.

Compounds of the disclosure may be prepared according to the process outlined in Scheme 1-x.

A suitably substituted compound of formula (1), a known compound or compound prepared by known methods wherein X¹ is an C₁₋₆ alkyl, is reacted with benzyl bromide in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and the like in the presence of a solvent such as ethanol, methanol, isopropanol, tetrahydrofuran, 1,4-dioxane, methylene chloride, N,N-dimethyl formamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (2). A compound of the formula (2) is reacted with a compound of the formula (3), a known compound or a compound prepared by known methods in which LG is a leaving group such as chlorine, bromine, iodine, mesylate, tosylate, and the like, in the presence of a base such as lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, and the like in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like, to provide a compound of the formula (4). A compound of the formula (4) is then treated with paraformaldehyde in the presence of an acid such as sulfuric acid, hydrochloric acid, and the like, in an the presence of acetic acid, and optionally in an organic solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (5). A compound of the formula (5) is then treated with a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, in an solvent such as water, methanol, ethanol, isopropanol, and the like, optionally with heating, and then treated with an acid such as sulfuric acid, hydrochloric acid, and the like, in a solvent such as water, methanol, ethanol, isopropanol, and the like, to provide a compound of the formula (6). A compound of the formula (6) is reacted with tert-butyldimethylchlorosilane in the presence of imidazole, in the presence of a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (7). Alternatively, a compound of the formula (6) is reacted with tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of a base such as pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (7).

A compound of the formula (7) is reacted with hydrogen gas in the presence of a palladium catalyst such as palladium on carbon, palladium on barium sulfate, palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, and the like, to provide a compound of the formula (8). A compound of the formula (8) is reacted with Di-tert-butyl dicarbonate in the presence of a base such as such as pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (9). A compound of the formula (9) is reacted with Tetra-n-butylammonium fluoride in the presence of solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (10).

A compound of the formula (10) is treated with carbon tetrabromide in the presence of triphenylphosphine, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (11). A compound of the formula (11) is reacted with a compound of the formula (12), a known compound or a compound prepared by known methods, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (13). A compound of the formula (13) is reacted with an acid such as trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, and the like, optionally in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (14).

A compound of the formula (14) is reacted with a compound of the formula (15), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16).

A compound of the formula (14) is reacted with a compound of the formula (17), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (18).

A compound of the formula (14) is reacted with a compound of the formula (19), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (20).

A compound of the formula (14) is reacted with a compound of the formula (21), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (22).

A compound of the formula (14) is reacted with a compound of the formula (23), a known compound or a compound prepared by known methods, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (24).

A compound of the formula (14) is reacted with a compound of the formula (25), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (26).

A suitably substituted compound of formula (27), a known compound or compound prepared by known methods wherein X¹ is an C₁₋₆ alkyl, is reacted with a compound of the formula (28), a known compound or a compound prepared by known methods in which LG is a leaving group such as chlorine, bromine, iodine, mesylate, tosylate, and the like, in the presence of a base such as lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, and the like in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like, to provide a compound of the formula (29). A compound of the formula (29) is then treated with paraformaldehyde in the presence of an acid such as sulfuric acid, hydrochloric acid, and the like, in an the presence of acetic acid, and optionally in an organic solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (30). A compound of the formula (30) is then treated with a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, in an solvent such as water, methanol, ethanol, isopropanol, and the like, optionally with heating, and then treated with an acid such as sulfuric acid, hydrochloric acid, and the like, in a solvent such as water, methanol, ethanol, isopropanol, and the like, to provide a compound of the formula (31). A compound of the formula (31) is treated with carbon tetrabromide in the presence of triphenylphosphine, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (32). A compound of the formula (32) is reacted with a compound of the formula (33), a known compound or a compound prepared by known methods, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (34).

A compound of the formula (29) is then reacted with iodine in the presence of a base such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, in the presence of a solvent such as tetrahydrofuran, ethyl ether, 1,4-dioxane, and the like to provide a compound of the formula (35). A compound of the formula (35) is reacted with a compound of the formula (36), a known compound or compound prepared by known methods, in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6 lutidine, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (37).

A compound of the formula (4) is then reacted with iodine in the presence of a base such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, in the presence of a solvent such as tetrahydrofuran, ethyl ether, 1,4-dioxane, and the like to provide a compound of the formula (38). A compound of the formula (38) is reacted with a compound of the formula (39), a known compound or compound prepared by known methods, in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6 lutidine, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (40). A compound of the formula (40) is reacted with hydrogen gas in the presence of a palladium catalyst such as palladium on carbon, palladium on barium sulfate, palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, and the like, to provide a compound of the formula (41).

A compound of the formula (41) is reacted with a compound of the formula (42), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (43).

A compound of the formula (41) is reacted with a compound of the formula (44), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (45).

A compound of the formula (41) is reacted with a compound of the formula (46), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (47).

A compound of the formula (41) is reacted with a compound of the formula (48), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (49).

A compound of the formula (41) is reacted with a compound of the formula (50), a known compound or a compound prepared by known methods, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (51).

A compound of the formula (41) is reacted with a compound of the formula (52), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (53).

A compound of the formula (4) is reacted with ruthenium chloride in the presence of sodium periodate in a solvent such as acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (54). A compound of the formula (54) is reacted with a compound of the formula (55), a known compound or compound prepared by known methods, wherein X² is a halogen, in the presence of a solvent such as ethyl ether, tetrahydrofuran, 1,4-dioxane and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (56). A compound of the formula (56) is reacted with ruthenium chloride in the presence of sodium periodate in a solvent such as acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (57). A compound of the formula (57) is reacted with a reducing agent such as lithium borohydride, sodium borohydride, sodium cyanoborohydride and the like, in a solvent such as methanol, ethanol, isopropanol, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (58). A compound of the formula (58) is treated with carbon tetrabromide in the presence of triphenylphosphine, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (59). A compound of the formula (59) is reacted with a compound of the formula (60), a known compound or a compound prepared by known methods, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (61).

A compound of the formula (62) is then converted to a compound of the formula (63), wherein LG is a mesylate, tosylate, nosylate, and the like, using methods that are known to one skilled in the art. Thus, a compound of the formula (62) is treated with a sulfonyl chloride such as methanesulfonyl chloride, toluenesulfonyl chloride p-nitrophenyl sulfonyl chloride, and the like, in the presence of a base such as triethylamine, diisopropyl amine, pyridine, 2,6-lutidine, and the like, in an organic solvent such as methylene chloride, dichloroethane, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like to provide a compound of the formula (63). A compound of the formula (63) is reacted with a compound of the formula (64), a known compound or a compound prepared by known methods, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (65).

A compound of the formula (4) is reacted with ruthenium chloride in the presence of sodium periodate in a solvent such as acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (66). A compound of the formula (66) is reacted with a compound of the formula (67), a known compound or compound prepared by known methods, wherein X² is a halogen, in the presence of a solvent such as ethyl ether, tetrahydrofuran, 1,4-dioxane and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (68). A compound of the formula (68) is reacted with ruthenium chloride in the presence of sodium periodate in a solvent such as acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (69). A compound of the formula (69) is reacted with a reducing agent such as lithium borohydride, sodium borohydride, sodium cyanoborohydride and the like, in a solvent such as methanol, ethanol, isopropanol, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (70). A compound of the formula (70) is reacted with tert-butyldimethylchlorosilane in the presence of imidazole, in the presence of a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (71). Alternatively, a compound of the formula (70) is reacted with tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of a base such as pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (71).

A compound of the formula (71) is reacted with hydrogen gas in the presence of a palladium catalyst such as palladium on carbon, palladium on barium sulfate, palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, and the like, to provide a compound of the formula (72). A compound of the formula (72) is reacted with Di-tert-butyl dicarbonate in the presence of a base such as such as pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (73). A compound of the formula (73) is reacted with Tetra-n-butylammonium fluoride in the presence of solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (74).

A compound of the formula (74) is treated with carbon tetrabromide in the presence of triphenylphosphine, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (75). A compound of the formula (75) is reacted with a compound of the formula (76), a known compound or a compound prepared by known methods, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (77). A compound of the formula (77) is reacted with an acid such as trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, and the like, optionally in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (78).

A compound of the formula (78) is reacted with a compound of the formula (79), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (80).

A compound of the formula (78) is reacted with a compound of the formula (81), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (82).

A compound of the formula (78) is reacted with a compound of the formula (83), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (84).

A compound of the formula (78) is reacted with a compound of the formula (85), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (86).

A compound of the formula (78) is reacted with a compound of the formula (87), a known compound or a compound prepared by known methods, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (88).

A compound of the formula (78) is reacted with a compound of the formula (89), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (90).

Diethanolamine (91) is reacted with 4-nitrobenzenesulfonyl chloride (NosCl) in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and the like in a solvent such as tetrahydrofuran, 1,4-dioxane, methylene chloride and the like to provide a compound of the formula (92). A compound of the formula (92) is then reacted with a compound of the formula (93), a known compound or one prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and the like, in a solvent such as acetonitrile, methanol, ethanol, dimethyl formamide, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (94). A compound of the formula (94) is reacted with a thiophenol in the presence of a base such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, in the presence of a solvent such as tetrahydrofuran, ethyl ether, 1,4-dioxane, acetonitrile and the like, optionally in the presence of dimethylsulfoxide, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (95).

A compound of the formula (96), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (97), a known compound or a compound prepared by known methods in which X³ is selected from the group consisting of chlorine, bromine, iodine, and methanetrifluorosulfonate, in the presence of a base such as sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, and the like, optionally in the presence of a base such as triethylamine, diisopropylethyl amine, pyridine, 2,6-lutidine, and the like, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0), and the like, in the presence of a solvent such as toluene, benzene, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (98). A compound of the formula (98) is reacted with an acid such as trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, and the like, optionally in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (99).

A compound of the formula (100), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (101), a known compound or a compound prepared by known methods in which X³ is selected from the group consisting of chlorine, bromine, iodine, and methanetrifluorosulfonate, in the presence of a base such as sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, and the like, optionally in the presence of a base such as triethylamine, diisopropylethyl amine, pyridine, 2,6-lutidine, and the like, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0), and the like, in the presence of a solvent such as toluene, benzene, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (102). A compound of the formula (102) is reacted with an acid such as trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, and the like, optionally in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (103).

A compound of the formula (104), a known compound or a compound prepared by known methods in which X⁴ is an C₁₋₆ alkyl, is reacted with di-tert-butyl dicarbonate in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and the like, in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (105). A compound of the formula (105) is reacted with a compound of the formula (106), a known compound or a compound prepared by known methods where in LG′ is a leaving group such as chlorine, bromine, iodine, mesylate, tosylate, and the like, in the presence of a base such as lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, and the like in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like, to provide a compound of the formula (107).

A compound of the formula (107) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, and the like in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (108). A compound of the formula (108) is then reacted with iodine in the presence of a base such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, in the presence of a solvent such as tetrahydrofuran, ethyl ether, 1,4-dioxane, and the like to provide a compound of the formula (109).

A compound of the formula (109) is reacted with a compound of the formula (110), a known compound or compound prepared by known methods, in an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylacetamide, and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6 lutidine, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (111). A compound of the formula (111) is reacted with an acid such as trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, and the like, optionally in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (112).

A compound of the formula (113) is reacted with ruthenium chloride in the presence of sodium periodate in a solvent such as acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (114). A compound of the formula (114) is reacted with a compound of the formula (115), a known compound or compound prepared by known methods, wherein X⁵ is a halogen, in the presence of a solvent such as ethyl ether, tetrahydrofuran, 1,4-dioxane and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (116). A compound of the formula (116) is reacted with ruthenium chloride in the presence of sodium periodate in a solvent such as acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation, to provide a compound of the formula (117). A compound of the formula (117) is reacted with a reducing agent such as lithium borohydride, sodium borohydride, sodium cyanoborohydride and the like, in a solvent such as methanol, ethanol, isopropanol, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (118).

A compound of the formula (7) is reacted with hydrogen gas in the presence of a palladium catalyst such as palladium on carbon, palladium on barium sulfate, palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, and the like, to provide a compound of the formula (119). A compound of the formula (119) is reacted with a compound of the formula (15), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (120). A compound of the formula (120) is reacted with tetra-n-butylammonium fluoride in the presence of solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (121). A compound of the formula (121) is treated with carbon tetrabromide in the presence of triphenylphosphine, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (122). A compound of the formula (122) is reacted with a compound of the formula (12), a known compound or a compound prepared by known methods, in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (123).

The Examples provided below provide representative methods for preparing exemplary compounds of the present invention. The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds of the present invention.

Examples

The practice of the invention is illustrated by the following non-limiting examples. The Examples provided below provide representative methods for preparing exemplary compounds of the present invention. The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds of the present invention.

In the examples that follow, ¹H-NMR spectra were obtained on a Varian Mercury 300-MHz NMR. Purity (%) and mass spectral data were determined with a Waters Alliance 2695 HPLC/MS (Waters Symmetry C18, 4.6×75 mm, 3.5 μm) with a 2996 diode array detector from 210-400 nm.

Example 1: Preparation of ethyl 1-benzylpiperidine-4-carboxylate: To a solution of ethyl piperidine-4-carboxylate (5.0 g, 31.8 mmol, 1.0 eq) and ethanol (15.0 mL), benzyl bromide (7.07 g, mmol, 1.3 eq) was added dropwise at 0° C. Following, triethylamine (1.06 g, 10.5 mmol, 1.5 eq) was added in one portion while at 0° C. The resulting mixture was allowed to warm to RT and stir overnight. The reaction was concentrated in vacuo to remove the presence of ethanol. The resulting residue was suspended in a mixture of ethyl acetate: D.I. water (20 mL:20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined extract was dried over Na₂SO₄, then filtered through a plug of silica gel and washed with ethyl acetate. The filtrated was concentrated in vacuo to give product that was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.20 (m, 5H), 4.14 (q, J=7.2 Hz, 2H), 3.51 (s, 2H), 2.87 (dt, J=3.5, 11.8 Hz, 2H), 2.29 (m, 1H), 2.04 (td, J=2.5, 11.4 Hz, 2H), 1.95-1.85 (m, 2H), 1.85-1.70 (m, 2H), 1.26 (t, J=7.1 Hz, 3H).

Example 2: Preparation of methyl 4-allyltetrahydro-2H-pyran-4-carboxylate: This reaction was performed in oven-dried glassware under a nitrogen atmosphere. To a solution of lithium diisopropylamide (1M, 1.20 equiv) in dry tetrahydrofuran (4.16 mL), methyl tetrahydro-2H-pyran-4-carboxylate (0.5 g, 3.47 mmol, 1.0 equiv), in 5 mL dry THF, was added dropwise during 0.5 hours at −78° C. The mixture was allowed to stir at this temperature for 1 hr followed by the addition of allyl bromide (0.457 g, 3.78 mmol, 1.1 eq) dropwise. The reaction mixture was allowed to warm to RT over a 1 hr period. The reaction was quenched with 10% HCl (while cooling in ice bath) until acidic (pH=2). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The extract was dried over Na₂SO₄ and then concentrated in vacuo to give product that was used in the next step without further purification. NMR (400 MHz, CDCl₃) δ 5.68-5.52 (m, 1H), 5.03-4.91 (m, 2H), 3.75 (dt, J=3.7, 11.8 Hz, 2H), 3.63 (s, 3H), 3.37 (td, J=2.1, 11.6 Hz, 2H), 2.21 (d, J=7.4 Hz, 2H), 2.03-1.95 (m, 2H), 1.53-1.40 (m, 2H).

Example 3: Preparation of ethyl 4-allyl-1-benzylpiperidine-4-carboxylate: This reaction was performed in oven-dried glassware under a nitrogen atmosphere. To a solution of ethyl 1-benzylpiperidine-4-carboxylate (6.24 g, 26.7 mmol, 1.0 eq) and dry THF (50 mL), lithium diisopropylamide (1M, 1.10 equiv) in dry tetrahydrofuran (29.3 mL) was added dropwise during 0.5 hours at −78° C. The mixture was allowed to stir at this temperature for 1 hr followed by the addition of allyl iodine (6.73 g, 3.78 mmol, 1.5 eq) dropwise. The reaction mixture was allowed to warm to RT and stir for 2 hr. The reaction was quenched with sat. aq. NH₄Cl until neutral pH (while cooling in ice bath). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined extract was dried over Na₂SO₄, then filtered through a plug of silica gel and washed with ethyl acetate. The filtrated was concentrated in vacuo to give product that was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.20 (m, 5H), 5.78-5.62 (m, 1H), 5.10-4.97 (m, 2H), 4.17 (q, J=7.1 Hz, 2H), 3.47 (s, 2H), 2.78-2.64 (m, 2H), 2.28 (d, J=7.4 Hz, 2H), 2.18-2.03 (m, 4H), 1.61-1.46 (m, 2H), 1.26 (t, J=7.1 Hz, 3H).

Example 4: Preparation of 3-(2-hydroxy ethyl)-2,8-dioxaspiro[4.5]decan-1-one: A mixture of glacial acetic acid (10.9 g, 180 mmol, 53.6 eq), paraformaldehyde (0.309 g, 10.3 mmol, 3.0 eq) and H₂SO₄ (0.191 g, 1.95 mmol, 0.57 eq) was stirred for 30 min at 70° C. before methyl 4-allyltetrahydro-2H-pyran-4-carboxylate (0.632 g, 3.43 mmol, 1.0 equiv) was added dropwise during 10 min. The reaction mixture was then maintained at 70˜80° C. and allowed to stir overnight. Acetic acid was removed under reduced pressure and the reaction was quenched with 10% NaHCO₃ solution. The mixture was then extracted with ethyl acetate (3×10 mL) and the combined organic phase was concentrated in vacuo to give a crude oil. The crude oil was used for next step without further purification.

A mixture of the crude oil (715 mg) and 30% NaOH (2.86 g NaOH, 4× crude oil) aqueous solution was refluxed for 2 hours. The mixture was cooled in an ice bath and excess 30% H₂SO₄ was added until acidic (pH<2). The resulting mixture was extracted with ethyl acetate (3×25 mL), the combined organic phase was washed with 10% NaHCO₃, (50 mL), brine (50 mL), dried over Na₂SO₄ and concentrated in vacuo to give a crude product which was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 4.57 (m, 1H), 3.91 (dt, J=4.5, 11.8 Hz, 1H), 3.79 (dt, J=4.5, 12.0 Hz, 1H), 3.66 (t, J=6.0 Hz, 2H), 3.54-3.44 (m, 1H), 3.43-3.34 (m, 1H), 3.13 (b, 1H), 2.41 (dd, J=6.1, 13.2 Hz, 1H), 2.01-1.91 (m, 1H), 1.89-1.64 (m, 4H), 1.54-1.44 (m, 1H), 1.42-1.33 (m, 1H).

Example 5: Preparation of 8-benzyl-3-(2-hydroxyethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: A mixture of glacial acetic acid (78.1 g, 1.3 mol, 53.6 eq), paraformaldehyde (2.21 g, 73.5 mmol, 3.0 eq) and H₂SO₄ (3.63 g, 37 mmol, 1.5 eq) was stirred for 30 min at 70° C. before ethyl 4-allyl-1-benzylpiperidine-4-carboxylate (7.03 g, 24.5 mmol, 1.0 equiv) was added dropwise during 10 min. The reaction mixture was then maintained at 70˜80° C. and allowed to stir overnight. Acetic acid was removed under reduced pressure and the reaction was quenched with 10% NaHCO₃ solution. The mixture was then extracted with ethyl acetate (3×40 mL) and the combined organic phase was concentrated in vacuo to give a crude oil. The crude oil was used for next step without further purification.

A mixture of the crude oil (7.07 mg) and 30% NaOH (28 g NaOH, 4× crude oil) aqueous solution was refluxed for 2 hours. The mixture was cooled in an ice bath and excess 30% H₂SO₄ was added until acidic (pH<2). The resulting mixture was the neutralized (pH=8-9) with sat. aq. NaHCO₃ solution and then extracted with ethyl acetate (3×100 mL), the combined organic phase was dried over Na₂SO₄ and concentrated in vacuo to give a crude product which was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.22 (m, 5H), 4.65 (m, 1H), 3.83 (t, J=5.6 Hz, 2H), 3.54 (s, 2H), 2.95-2.84 (m, 1H), 2.83-2.73 (m, 1H), 2.42 (dd, J=6.1, 13.0 Hz, 1H), 2.30-2.07 (m, 4H), 2.00-1.84 (m, 3H), 1.75-1.59 (m, 2H), 1.58-1.48 (m, 1H).

Example 6: Preparation of 8-benzyl-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: To a solution of 8-benzyl-3-(2-hydroxyethyl)-2-oxa-8-azaspiro[4.5]decan-1-one (10.0 g, 34.6 mmol, 1.0 eq.), imidazole (2.47 g, 36.3 mmol, 1.05 eq.) and dichloromethane (70 mL), was added a solution of tert-Butyldimethylsilyl chloride (1M, 5.47 g, 36.3 mmol, 1.05 eq.) in dichloromethane (36.3 mL). The reaction was allowed to stir at RT for 2 hr, before being quenched with D.I. water (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic phase was dried over Na₂SO₄ and concentrated in vacuo to give a crude product which was further purified by column chromatography (Ethyl acetate/Hexanes, 0%˜20%). ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.11 (m, 5H), 4.52 (m, 1H), 3.73-3.65 (m, 2H), 3.46 (s, 2H), 2.87-2.76 (m, 1H), 2.72 (dt, J=4.5, 11.8 Hz, 1H), 2.31 (dd, J=6.2, 12.9 Hz, 1H), 2.22-2.08 (m, 1H), 2.08-1.97 (m, 2H), 1.91-1.70 (m, 3H), 1.62 (dd, J=9.8, 12.8 Hz, 1H), 1.59-1.50 (m, 1H), 1.49-1.38 (m, 1H), 0.83 (s, 9H), 0.00 (s, 6H).

Example 7: Preparation of tert-butyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A mixture of 8-benzyl-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one (4.77 g, 11.8 mmol, 1 eq.), Pd/C (954 mg, 20% wt) and MeOH (79 mL) was stirred at RT under 1 atm of H₂ (filled balloon) overnight. The mixture was filtered through a plug of Celite, washed with MeOH (50 mL) and concentrated in vacuo to give a crude oil. The crude oil (3.78 g) was dissolved in dichloromethane (79 mL) and cooled to 0° C. before the addition of Di-tort-butyl dicarbonate (2.83 g, 13.0 mmol, 1.1 eq) and trimethylamine (1.8 g, 17.7 mmol, 1.5 eq.). The reaction was allowed to warm to RT and stir for 45 min. At this point the reaction was diluted with sat. aq. NaHCO₃ solution and then extracted with ethyl acetate (3×50 mL), the combined organic phase was dried over Na₂SO₄ and concentrated in vacuo to give a crude product which was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 4.57 (m, 1H), 3.91 (b, 1H), 3.77 (b, 1H), 3.73-3.66 (m, 2H), 3.17-3.05 (m, 1H), 3.04-2.93 (m, 1H), 2.31 (dd, J=6.2, 13.0 Hz, 1H), 1.96-1.81 (m, 2H), 1.81-1.64 (m, 3H), 1.59-1.48 (m, 1H), 1.48-1.32 (m, 10H), 0.83 (s, 9H), 0.00 (s, 6H).

Example 8: Preparation of tert-butyl 3-(2-hydroxyethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: To a solution of tert-butyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (4.88 g, 11.8 mmol, 1 eq.) and THF (70 mL) was added tetra-n-butylammonium fluoride (3.24 g, 12.4 mmol, 1.05 eq,); using THF (10 mL) to complete transfer. The resulting solution was allowed to stir at RT for 30 min before being concentrated in vacuo to give a crude product which was further purified by column chromatography (MeOH/DCM, 0%˜10%). ¹H NMR (400 MHz, CDCl₃) δ 4.67 (m, 1H), 3.95 (dt, J=5.0, 13.6 Hz, 1H), 3.87-3.73 (m, 3H), 3.23-3.10 (m, 1H), 3.09-2.98 (m, 1H), 2.39 (dd, J=6.0, 13.0 Hz, 1H), 1.99-1.84 (m, 4H), 1.83-1.68 (m, 2H), 1.63-1.53 (m, 1H), 1.53-1.36 (m, 10H).

Example 9: Preparation of 3-(2-bromoethyl)-2,8-dioxaspiro[4.5]decan-1-one: A solution of 3-(2-hydroxyethyl)-2,8-dioxaspiro[4.5]decan-1-one (0.320 g, 1.60 mmol, 1 eq.) and THF (15 mL) was cooled to 0° C. before triphenylphosphine (0.630 g. 2.4 mmol, 1.5 eq.) and carbon tetrabromide (0.795 g, 2.4 mmol, 1.5 eq.) were sequentially added to the solution. The reaction solution was allowed to warm to RT and stir overnight. The resulting mixture was then filtered and concentrated in vacuo to give a crude mixture. This mixture was suspended in diethyl ether (50 mL) and filtered 2× using diethyl ether to wash the filter cakes. The final filtrate was loaded onto Celite in vacuo and further purified by column chromatography (ethyl acetate/hexanes, 0%˜40%). ¹H NMR (400 MHz, CDCl₃) δ 4.67 (m, 1H), 4.04 (dt, J=4.6, 11.8 Hz, 1H), 3.91 (dt, J=4.6, 12.1 Hz, 1H), 3.60 (m, 1H), 3.56-3.45 (m, 3H), 2.50 (dd, J=6.1, 12.9 Hz, 1H), 2.30-2.02 (m, 3H), 1.91 (m, 1H), 1.76 (dd, J=9.8, 13.0 Hz, 1H), 1.64-1.55 (m, 1H), 1.52-1.44 (m, 1H).

Example 10: Preparation of tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The title compound was prepared according to the procedure for 3-(2-bromoethyl)-2,8-dioxaspiro[4.5]decan-1-one, except tert-butyl 3-(2-hydroxyethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was substituted for 3-(2-hydroxyethyl)-2,8-dioxaspiro[4.5]decan-1-one: ¹H NMR (400 MHz, CDCl₃) δ 4.68 (m, 1H), 3.97 (dt, J=5.0, 13.5 Hz, 1H), 3.83 (dt, J=5.0, 13.7 Hz, 1H), 3.54 (dd, J=5.3, 7.5 Hz, 2H), 3.27-3.14 (m, 1H), 3.13-3.01 (m, 1H), 2.42 (dd, J=6.0, 13.0 Hz, 1H), 2.31-2.20 (m, 1H), 2.20-2.09 (m, 1H), 2.01-1.90 (m, 1H), 1.89-1.78 (m, 1H), 1.74 (dd, J=9.8, 12.8 Hz, 1H), 1.66-1.56 (m, 1H), 1.54-1.36 (m, 10H).

Example 11: Preparation of 8-benzyl-3-(2-bromoethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate: A solution of 3-(2-hydroxyethyl)-2,8-dioxaspiro[4.5]decan-1-one (2.07 g, 7.16 mmol, 1 eq.) and THF (70 mL) was cooled to 0° C. before triphenylphosphine (2.83 g. 10.8 mmol, 1.5 eq.) and carbon tetrabromide (3.58 g, 10.8 mmol, 1.5 eq.) were sequentially added to the solution. The reaction solution was allowed to warm to RT and stir overnight. The resulting mixture was then filtered and concentrated in vacuo to give a crude mixture. This mixture was suspended in diethyl ether (50 mL) and filtered 2× using diethyl ether to wash the filter cakes. The final filtrate was loaded onto Celite in vacuo and further purified by column chromatography on a C18 column. (ACN/H₂O, 0%˜100%, w/0.1% formic acid). ¹H NMR (400 MHz, MeOD) δ 7.53 (b, 2H), 7.47 (b, 3H), 4.75 (m, 1H), 4.27 (s, 2H), 3.64-3.47 (m, 3H), 3.34 (m, 1H), 3.19 (b, 1H), 3.08 (b, 1H), 2.52 (m, 1H), 2.35-2.15 (m, 3H), 2.15-1.97 (m, 2H), 1.96-1.81 (m, 2H).

Example 12: Preparation of 3-(2-(4-phenylpiperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one: A solution of 3-(2-bromoethyl)-2,8-dioxaspiro[4.5]decan-1-one (0.050 g, 0.190 mmol, 1 eq.), THF (4 mL) and 1-phenylpiperazine (0.065 g, 0.399 mmol, 2.1 eq.) was heated and stirred at 60° C. for 3 days. The resulting mixture was then filtered and concentrated in vacuo to give a crude residue that was further purified by column chromatography (methanol/dichloromethane, 0%˜10%). ¹H NMR (400 MHz, CDCl₃) δ 7.27 (m, 2H), 6.93 (d, J=8.3 Hz, 2H), 6.86 (t, J=7.3 Hz, 1H), 4.58 (m, 1H), 4.06 (dt, J=4.6, 11.9 Hz, 1H), 3.93 (dt, J=4.6, 12.0 Hz, 1H), 3.61 (m, 1H), 3.51 (m, 1H), 3.21 (t, J=5.0 Hz, 4H), 2.70-2.52 (m, 6H), 2.47 (dd, J=6.0, 12.8 Hz, 1H), 2.11 (m, 1H), 2.01-1.83 (m, 3H), 1.79 (dd, J=9.7, 13.1 Hz, 1H), 1.65-1.54 (m, 1H), 1.54-1.45 (m, 1H); MS (LC/MS, M+H⁺): 344.8.

Example 13: Preparation of 3-(2-(4-(4-hydroxyphenyl)piperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 3-(2-(4-phenylpiperazin-1-yl)ethyl)-2,8-dioxaspiro[4.5]decan-1-one, except 4-(piperazin-1-yl)phenol was substituted for 1-phenylpiperazine: ¹H NMR (400 MHz, CDCl₃) δ 6.74 (d, J=8.9 Hz, 2H), 6.63 (d, J=8.9 Hz, 2H), 4.45 (m, 1H), 3.97 (dt, J=4.6, 11.8 Hz, 1H), 3.83 (dt, J=4.5, 12.3 Hz, 1H), 3.51 (m, 1H), 3.42 (m, 1H), 3.00 (t, J=4.7 Hz, 4H), 2.67-2.42 (m, 6H), 2.35 (dd, J=6.1, 12.1 Hz, 1H), 2.00 (m, 1H), 1.92-1.74 (m, 3H), 1.67 (dd, J=9.6, 12.9 Hz, 1H), 1.52-1.43 (m, 1H), 1.43-1.34 (m, 1H); MS (LC/MS, M+H⁺): 360.8.

Example 14: Preparation of 8-benzyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: A solution of 8-benzyl-3-(2-bromoethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate (0.545 g, 1.37 mmol, 1 eq.), THF (13.7 mL), 1-(p-tolyl)piperazine (0.507 g, 2.88 mmol, 2.1 eq.) and triethylamine (0.107 g, 1.5 mmol, 1.1 eq.) was heated and stirred at 60° C. for 3 days. The resulting mixture was then filtered and concentrated in vacuo to give a crude residue that was further purified by column chromatography (methanol/dichloromethane, 0%˜10%). NMR (400 MHz, CDCl₃) δ 7.39-7.23 (m, 5H), 7.10 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 4.53 (m, 1H), 3.54 (s, 2H), 3.17 (t, J=5.0 Hz, 4H), 2.95-2.85 (m, 1H), 2.84-2.75 (m, 1H), 2.70-2.49 (m, 6H), 2.40 (dd, J=6.2, 12.8 Hz, 1H), 2.30 (s, 3H), 2.27-2.05 (m, 3H), 2.01-1.79 (m, 3H), 1.76-1.58 (m, 2H), 1.58-1.46 (m, 1H); MS (LC/MS, M+H⁺): 447.8.

Example 15: Preparation of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: A mixture of 8-benzyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one (445 mg, 0.993 mmol, 1 eq.), Pd/C (90 mg, 20% wt) and EtOH (6.6 mL) was stirred at RT under 1 atm of H₂ (filled balloon) for 48 hrs. The mixture was filtered through a plug of Celite, washed with MeOH (50 mL) and concentrated in vacuo to give a crude oil. ¹H NMR (400 MHz, MeOD) δ 6.95 (d, J=8.2 Hz, 2H), 6.77 (d, J=8.5 Hz, 2H), 4.56 (m, 1H), 3.47 (m, 1H), 3.28-3.18 (m, 1H), 3.17-3.09 (m, 1H), 3.08-2.96 (m, 5H), 2.66-2.46 (m, 6H), 2.42 (dd, J=6.0, 13.0 Hz, 1H), 2.14 (s, 3H), 2.10-2.00 (m, 1H), 2.00-1.91 (m, 1H), 1.91-1.80 (m, 4H), 1.80-1.70 (m, 1H); MS (LC/MS, M+H⁺): 357.8.

Example 16: Preparation of methyl 1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A solution of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one (0.05 g, 0.14 mmol, 1 eq.), dichloromethane (2 mL) and triethylamine (0.44 g, 0.41 mmol, 3 eq.) was cooled to 0° C. before methyl chloroformate (0.027 g. 0.28 mmol, 2 eq.) was added to the solution. The reaction solution was allowed to warm to RT and stir for 3 hours. The reaction was diluted with dichloromethane and loaded onto Celite in vacuo and further purified by column chromatography on a C18 column. (ACN/H₂O, 0%˜100%, w/0.1% formic acid). The resulting formate acid salt was dissolved in MeOH (2 mL) and Amberlite IRA-400(OH) resin was added. This mixture was allowed to stir at RT for 30 min and then filtered and concentrated in vacuo to afford pure free based product. ¹H NMR (400 MHz, CDCl₃) δ 7.08 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.59 (m, 1H), 4.02 (b, 1H), 3.85 (b, 1H), 3.72 (s, 3H), 3.35-3.24 (m, 1H), 3.23-3.10 (m, 5H), 2.71-2.50 (m, 6H), 2.38 (dd, J=6.0, 12.8 Hz, 1H), 2.28 (s, 3H), 2.07-1.72 (m, 5H), 1.69-1.47 (m, 2H); MS (LC/MS, M+H⁺): 415.8.

Example 17: Preparation of 8-acetyl-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for methyl 1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except acetic anhydride was substituted for methyl chloroformate: NMR (400 MHz, CDCl₃) δ 7.08 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 4.60 (m, 1H), 4.19 (m, 0.5H), 4.04-3.84 (m, 1H), 3.72 (m, 0.5H), 3.45-3.22 (m, 2H), 3.15 (t, J=4.8 Hz, 4H), 2.70-2.49 (m, 6H), 2.43-2.32 (m, 1H), 2.27 (s, 3H), 2.10 (s, 3H), 2.05-1.72 (m, 5H), 1.69-1.49 (m, 2H); MS (LC/MS, M+H⁺): 399.8.

Example 18: Preparation of N-methyl-1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxamide: The title compound was prepared according to the procedure for methyl 1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except N-methyl-1H-imidazole-1-carboxamide was substituted for methyl chloroformate: NMR (400 MHz, MeOD) δ 6.96 (d, J=8.3 Hz, 2H), 6.78 (d, J=8.2 Hz, 2H), 4.52 (m, 1H), 3.79 (dt, J=4.7, 13.8 Hz, 1H), 3.68 (dt, J=4.5, 13.8 Hz, 1H), 3.22 (m, 1H), 3.16-2.86 (m, 6H), 2.63 (s, 3H), 2.59-2.36 (m, 7H), 2.15 (s, 3H), 1.91-1.67 (m, 3H), 1.66-1.50 (m, 2H), 1.50-1.38 (m, 1H); MS (LC/MS, M+H⁺): 414.8.

Example 20: Preparation of tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A mixture of tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.500 g, 1.38 mmol, 1 eq.), ACN (7 mL), 1-(2-isopropylphenyl)piperazine (0.337 g, 1.65 mmol, 1.2 eq.) and K₂CO₃ (0.954 g, 6.9 mmol, 5 eq.) was heated and stirred at 80° C. for 3 days. The resulting mixture was then filtered and concentrated in vacuo to give a crude residue that was further purified by column chromatography (methanol/dichloromethane, 0%˜10%). ¹H NMR (400 MHz, CDCl₃) δ 7.16 (dd, J=1.6, 7.4 Hz, 1H), 7.09-6.94 (m, 3H), 4.49 (m, 1H), 3.89 (b, 1H), 3.75 (b, 1H), 3.40 (sep, J=6.9 Hz, 1H), 3.09 (m, 1H), 2.98 (m, 1H), 2.81 (t, J=4.6 Hz, 4H), 2.65-2.39 (m, 5H), 2.30 (dd, J=6.1, 12.8 Hz, 1H), 1.99-1.60 (m, 5H), 1.51 (m, 1H), 1.46-1.29 (m, 11H), 1.12 (s, 3H), 1.10 (s, 6H); MS (LC/MS, M+H⁺): 485.8

Example 21: Preparation of tert-butyl 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The title compound was prepared according to the procedure for tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except 1,2,3,4-tetrahydroisoquinoline hydrochloride was substituted for 1-(2-isopropylphenyl)piperazine: NMR (400 MHz, CDCl₃) δ 7.07-6.96 (m, 3H), 6.95-6.87 (m, 1H), 4.53 (m, 1H), 3.87 (b, 1H), 3.72 (b, 1H), 3.60-3.46 (m, 2H), 3.06 (m, 1H), 2.95 (m, 1H), 2.80 (t, J=5.8 Hz, 2H), 2.64 (t, J=6.0 Hz, 2H), 2.58 (t, J=7.3 Hz, 2H), 2.28 (dd, J=6.1, 12.9 Hz, 1H), 1.97-1.75 (m, 3H), 1.74-1.58 (m, 2H), 1.54-1.26 (m, 11H); MS (LC/MS, M+H⁺): 414.8

Example 22: Preparation of tert-butyl 1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A solution of tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.5 g, 4.11 mmol, 1.1 eq.), THF (36 mL), 1-(p-tolyl)piperazine (0.660 g, 3.74 mmol, 1 eq.) and triethylamine (0.416 g, 4.11 mmol, 1.1 eq.) was heated and stirred at 70° C. for 3 days. The resulting mixture was then filtered and concentrated in vacuo to give a crude residue that was further purified by column chromatography (methanol/dichloromethane, 0%˜10%). ¹H NMR (400 MHz, CDCl₃) δ 7.05 (d, J=8.3 Hz, 2H), 6.82 (d, J=8.5 Hz, 2H), 4.55 (m, 1H), 3.96 (m, 1H), 3.81 (m, 1H), 3.22-2.98 (m, 6H), 2.67-2.45 (m, 6H), 2.36 (dd, J=6.2, 12.9 Hz, 1H), 2.25 (s, 3H), 2.00-1.66 (m, 5H), 1.57 (m, 1H), 1.53-1.34 (m, 10H); MS (LC/MS, M+H⁺): 457.8

Example 23: Preparation of tert-butyl 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A solution of tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.5 g, 1.38 mmol, 1. eq.), THF (12 mL), 2-methyl-7-(piperazin-1-yl)-1H-benzo[d]imidazole (0.549 g, 1.65 mmol, 1.2 eq.) and triethylamine (0.500 g, 4.95 mmol, 3.5 eq.) was heated and stirred at 70° C. for 3 days. The resulting mixture was then filtered and concentrated in vacuo to give a crude residue that was first purified by column chromatography (methanol/dichloromethane, 0%˜10%). The resulting fractions were further purified by column chromatography on a C18 column. (ACN/H₂O, 0%˜100%, w/0.1% NH₄OH) NMR (400 MHz, CDCl₃) δ 7.16-6.97 (m, 2H), 6.65 (m, 1H), 4.54 (m, 1H), 3.98 (m, 1H), 3.83 (m, 1H), 3.40 (b, 4H), 3.17 (t, J=11.1 Hz, 1H), 3.06 (t, J=11.5 Hz, 1H), 2.68-2.42 (m, 9H), 2.36 (dd, J=6.2, 13.0 Hz, 1H), 1.99-1.66 (m, 5H), 1.58 (m, 1H), 1.54-1.33 (m, 10H); MS (LC/MS, M+H⁺): 497.8

Example 24: Preparation of tert-butyl 3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The title compound was prepared according to the procedure for tert-butyl 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except 4-(2-(piperazin-1-yl)phenyl)morpholine was substituted for 2-methyl-7-(piperazin-1-yl)-1H-benzo[d]imidazole: ¹H NMR (400 MHz, CDCl₃) δ 6.94-6.87 (m, 2H), 6.87-6.78 (m, 2H), 4.51 (m, 1H), 3.90 (m, 1H), 3.81-3.66 (m, 5H), 3.34-2.84 (m, 10H), 2.67-2.37 (m, 6H), 2.31 (dd, J=6.2, 12.9 Hz, 1H), 1.93-1.59 (m, 5H), 1.52 (m, 1H), 1.47-1.30 (m, 10H); MS (LC/MS, M+H⁺): 528.8

Example 25: Preparation of 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: To a solution of tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.450 g, 0.930 mmol, 1 eq.) in dichloromethane (3 mL) at 0° C. was added trifluoroacetic acid (3 mL). The reaction was allowed to stir at RT for 30 min before being diluted with MeOH and concentrated in vacuo to afford the product as a TFA salt. The resulting TFA salt was dissolved in MeOH (2 mL) and Amberlite IRA-400(OH) resin was added. This mixture was allowed to stir at RT for 30 min and then filtered and concentrated in vacuo to afford pure free based product. ¹H NMR (400 MHz, MeOD) δ 7.16 (d, J=7.5 Hz, 1H), 7.07-6.93 (m, 3H), 4.50 (m, 1H), 3.44 (sep, J=6.9 Hz, 1H), 2.99 (dt, J=4.3, 12.6 Hz, 1H), 2.89 (dt, J=4.3, 13.2 Hz, 1H), 2.82 (t, J=4.7 Hz, 4H), 2.74-2.37 (m, 9H), 1.91-1.78 (m, 3H), 1.77-1.50 (m, 3H), 1.42 (m, 1H), 1.12 (s, 3H), 1.10 (s, 3H); MS (LC/MS, M+H⁺): 385.8

Example 26: Preparation of 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one, except tert-butyl 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was substituted for tert-butyl 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: NMR (400 MHz, MeOD) δ 7.18-7.09 (m, 3H), 7.09-7.03 (m, 1H), 4.64 (m, 1H), 3.68 (s, 2H), 3.25 (dt, J=5.0, 13.1 Hz, 1H), 3.10 (dt, J=5.0, 13.4 Hz, 1H), 2.99-2.88 (m, 3H), 2.85-2.61 (m, 5H), 2.55 (dd, J=6.1, 12.9 Hz, 1H), 2.09-1.95 (m, 3H), 1.90-1.70 (m, 3H), 1.63 (m, 1H); MS (LC/MS, M+H⁺): 314.8

Example 27: Preparation of 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate: A solution of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one (0.05 g, 0.14 mmol, 1 eq.), dichloromethane (2 mL) and triethylamine (0.44 g, 0.41 mmol, 3 eq.) was cooled to 0° C. before methanesulfonyl chloride (0.032 g. 0.28 mmol, 2 eq.) was added to the solution. The reaction solution was allowed to warm to RT and stir for 3 hours. The reaction was diluted with dichloromethane and loaded onto Celite in vacuo and further purified by column chromatography on a C18 column. (ACN/H₂O, 0%˜100%, w/0.1% formic acid). ¹H NMR (400 MHz, DMSO) δ 7.01 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.5 Hz, 2H), 4.59 (m, 1H), 3.58-3.45 (m, 1H), 3.44-3.33 (m, 1H), 3.13-2.95 (m, 5H), 2.88 (s, 3H), 2.86-2.78 (m, 1H), 2.62-2.31 (m, 7H), 2.19 (s, 3H), 1.97-1.57 (m, 7H); MS (LC/MS, M+H⁺): 435.8

Example 28: Preparation of 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 3-(2-(4-(2-isopropylphenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one was substituted for 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: NMR (400 MHz, MeOD) δ 7.34-7.27 (m, 1H), 7.23-7.08 (m, 3H), 4.67 (m, 1H), 3.70 (dt, J=4.8, 12.3 Hz, 1H), 3.61-3.47 (m, 2H), 3.40-3.09 (m, 11H), 3.04 (m, 1H), 2.88 (s, 3H), 2.56 (dd, J=6.4, 12.8 Hz, 1H), 2.29-2.10 (m, 2H), 2.05 (m, 1H), 1.96-1.80 (m, 3H), 1.75 (m, 1H), 1.24 (s, 3H), 1.22 (s, 3H); MS (LC/MS, M+H⁺): 463.7

Example 29: Preparation of 8-(methylsulfonyl)-3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 3-(2-(4-(2-morpholinophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one was substituted for 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: NMR (400 MHz, MeOD) δ 7.13-6.90 (m, 4H), 4.67 (m, 1H), 3.86 (t, J=4.6 Hz, 4H), 3.70 (dt, J=4.7, 12.3 Hz, 1H), 3.61-3.08 (m, 16H), 3.04 (m, 1H), 2.88 (s, 3H), 2.56 (dd, J=5.9, 13.0 Hz, 1H), 2.29-2.11 (m, 2H), 2.05 (m, 1H), 1.97-1.81 (m, 3H), 1.75 (m, 1H); MS (LC/MS, M+H⁺): 507.2

Example 30: Preparation of 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 3-(2-(4-(2-methyl-1H-benzo[d]imidazol-7-yl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one was substituted for 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: NMR (400 MHz, MeOD) δ 7.47-7.26 (m, 2H), 7.04 (d, J=6.7 Hz, 1H), 4.69 (m, 1H), 3.79-3.28 (m, 12H), 3.14 (m, 1H), 3.01 (m, 1H), 2.87 (s, 3H), 2.79 (s, 3H), 2.58 (dd, J=5.9, 12.9 Hz, 1H), 2.38-2.14 (m, 2H), 2.12-1.98 (m, 1H), 1.96-1.80 (m, 3H), 1.75 (m, 1H); MS (LC/MS, M+H⁺): 476.2

Example 31: Preparation of 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 3-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one was substituted for 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: ¹H NMR (400 MHz, MeOD) δ 7.31-7.21 (m, 3H), 7.20-7.15 (m, 1H), 4.67 (m, 1H), 4.26 (s, 2H), 3.70 (dt, J=4.9, 12.3 Hz, 1H), 3.53 (dt, J=5.2, 12.5 Hz, 1H), 3.39 (t, J=6.2 Hz, 2H), 3.31-3.10 (m, 5H), 3.03 (m, 1H), 2.88 (s, 3H), 2.56 (dd, J=6.0, 12.9 Hz, 1H), 2.30-2.12 (m, 2H), 2.05 (m, 1H), 1.97-1.80 (m, 3H), 1.75 (m, 1H); MS (LC/MS, M+H⁺): 392.7.

Example 32: Preparation of 8-(phenylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except benzenesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 7.69 (m, 2H), 7.53 (m, 1H), 7.46 (m, 2H), 7.00 (d, J=8.3 Hz, 2H), 6.75 (d, J=8.5 Hz, 2H), 4.44 (m, 1H), 3.46 (m, 1H), 3.22 (m, 1H), 3.10 (t, J=4.7 Hz, 4H), 2.97 (m, 1H), 2.87 (m, 1H), 2.75-2.44 (m, 6H), 2.19 (s, 3H), 2.12 (dd, J=6.1, 13.0 Hz, 1H), 2.02-1.77 (m, 4H), 1.72-1.53 (m, 3H); MS (LC/MS, M+H⁺): 498.2.

Example 33: Preparation of 8-((4-methoxyphenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 4-methoxybenzenesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J=9.0 Hz, 2H), 6.99 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.9 Hz, 2H), 6.75 (d, J=8.6 Hz, 2H), 4.45 (m, 1H), 3.80 (s, 3H), 3.42 (m, 1H), 3.18 (m, 1H), 3.04 (t, J=4.9 Hz, 4H), 2.95 (m, 1H), 2.86 (m, 1H), 2.57-2.39 (m, 6H), 2.19 (s, 3H), 2.11 (dd, J=6.1, 12.9 Hz, 1H), 2.01-1.86 (m, 2H), 1.86-1.50 (m, 5H); MS (LC/MS, M+H⁺): 528.2.

Example 34: Preparation of 8-((4-chlorophenyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 4-chlorobenzenesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=8.6 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.6 Hz, 2H), 4.40 (m, 1H), 3.37 (m, 1H), 3.10 (m, 1H), 3.02 (t, J=4.7 Hz, 4H), 2.96 (m, 1H), 2.87 (m, 1H), 2.59-2.34 (m, 6H), 2.13 (s, 3H), 2.06 (dd, J=5.9, 12.9 Hz, 1H), 1.95-1.81 (m, 2H), 1.81-1.67 (m, 2H), 1.66-1.49 (m, 3H); MS (LC/MS, M+H⁺): 532.2.

Example 35: Preparation of 8-((tetrahydro-2H-pyran-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except tetrahydro-2H-pyran-4-sulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column (MeOH/DCM, 0%˜10%): NMR (400 MHz, CDCl₃) δ 7.08 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.5 Hz, 2H), 4.60 (m, 1H), 4.08 (dd, J=3.6, 11.5 Hz, 2H), 3.80 (m, 1H), 3.57-3.42 (m, 4H), 3.41-3.30 (m, 3H), 3.22-3.06 (m, 5H), 2.69-2.47 (m, 6H), 2.30 (dd, J=6.1, 12.9 Hz, 1H), 2.27 (s, 3H), 2.03-1.65 (m, 9H); MS (LC/MS, M+H⁺): 506.2.

Example 36: Preparation of 8-(thiophen-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except thiophene-2-sulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): NMR (400 MHz, CDCl₃) δ 7.53 (dd, J=1.2, 5.0 Hz, 1H), 7.46 (dd, 1.3, 3.8 Hz, 1H), 7.06 (dd, J=3.8, 5.0 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.5 Hz, 2H), 4.46 (m, 1H), 3.49 (m, 1H), 3.24 (m, 1H), 3.12-2.97 (m, 5H), 2.92 (m, 1H), 2.61-2.41 (m, 6H), 2.19 (s, 3H), 2.14 (dd, J=6.0, 13.0 Hz, 1H), 2.04-1.88 (m, 2H), 1.88-1.73 (m, 2H), 1.73-1.57 (m, 3H); MS (LC/MS, M+H⁺): 504.1.

Example 37: Preparation of 4((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)benzonitrile: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 4-cyanobenzenesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): NMR (400 MHz, CDCl₃) δ 7.89 (d, J=8.1 Hz, 2H), 7.85 (d, 7.8 Hz, 2H), 7.08 (d, J=8.2 Hz, 2H), 6.84 (d, J=8.5 Hz, 2H), 4.57 (m, 1H), 3.53 (m, 1H), 3.24 (m, 2H), 3.20-3.07 (m, 5H), 2.68-2.48 (m, 6H), 2.28 (s, 3H), 2.21 (dd, J=6.0, 13.0 Hz, 1H), 2.08-1.97 (m, 2H), 1.97-1.65 (m, 5H); MS (LC/MS, M+H⁺): 523.2.

Example 38: Preparation of 8-((6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column (MeOH/DCM, 0%˜10%): NMR (400 MHz, CDCl₃) δ 7.90 (d, J=4.5 Hz, 1H), 7.11-7.02 (m, 3H), 6.84 (d, J=8.6 Hz, 2H), 4.57 (m, 1H), 3.74 (m, 1H), 3.52 (m, 1H), 3.26 (m, 1H), 3.20-3.06 (m, 5H), 2.67-2.47 (m, 6H), 2.32-2.21 (m, 4H), 2.13-1.97 (m, 2H), 1.97-1.82 (m, 2H), 1.82-1.65 (m, 3H); MS (LC/MS, M+H⁺): 578.1.

Example 39: Preparation of 8-(((methylsulfonyl)methyl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except (methylsulfonyl)methanesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J=8.3 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 4.61 (m, 1H), 4.45 (s, 2H), 3.89 (m, 1H), 3.66 (m, 1H), 3.45 (m, 1H), 3.34 (m, 1H), 3.23 (s, 3H), 3.17 (t, J=4.9 Hz, 4H), 2.73-2.52 (m, 6H), 2.37 (dd, J=6.1, 12.9 Hz, 1H), 2.28 (s, 3H), 2.15-1.85 (m, 4H), 1.85-1.65 (m, 3H); MS (LC/MS, M+H⁺): 514.2.

Example 40: Preparation of 2-((1-oxo-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)acetonitrile: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except cyanomethanesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J=8.3 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 4.64 (m, 1H), 4.02-3.91 (m, 3H), 3.69 (m, 1H), 3.58 (m, 1H), 3.48 (m, 1H), 3.18 (t, J=4.9 Hz, 4H), 2.73-2.54 (m, 6H), 2.34 (dd, J=6.1, 13.0 Hz, 1H), 2.29 (s, 3H), 2.13-2.02 (m, 2H), 2.02-1.89 (m, 2H), 1.89-1.71 (m, 3H); MS (LC/MS, M+H⁺): 461.2.

Example 41: Preparation of 8-(propylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 1-propanesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 4.61 (m, 1H), 3.73 (m, 1H), 3.48-3.35 (m, 2H), 3.34-3.25 (m, 1H), 3.16 (t, J=4.8 Hz, 4H), 2.92 (m, 2H), 2.69-2.50 (m, 6H), 2.30 (dd, J=6.0, 12.9 Hz, 1H), 2.28 (s, 3H), 2.07-1.65 (m, 9H), 1.07 (t, J=7.4 Hz, 3H); MS (LC/MS, M+H⁺): 464

Example 42: Preparation of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((trifluoromethyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except trifluoromethanesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 6.96 (d, J=8.3 Hz, 2H), 6.72 (d, J=8.5 Hz, 2H), 4.50 (m, 1H), 3.87 (m, 1H), 3.70-3.23 (b, 3H), 3.03 (t, J=4.9 Hz, 4H), 2.56-2.38 (m, 6H), 2.19 (dd, J=6.2, 12.9 Hz, 1H), 2.15 (s, 3H), 1.98-1.86 (m, 2H), 1.86-1.52 (m, 5H); MS (LC/MS, M+H⁺): 490

Example 43: Preparation of 8-(isopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 2-propanesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 6.95 (d, J=8.2 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 4.47 (m, 1H), 3.67 (m, 1H), 3.44 (m, 1H), 3.35 (m, 1H), 3.25 (m, 1H), 3.12-2.94 (m, 5H), 2.58-2.36 (m, 6H), 2.18 (dd, J=6.0, 12.9 Hz, 1H), 2.14 (s, 3H), 1.92-1.71 (m, 4H), 1.71-1.45 (m, 3H); MS (LC/MS, M+H⁺): 464

Example 44: Preparation of 8-(cyclopropylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except cyclopropanesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 7.08 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 4.61 (m, 1H), 3.78 (m, 1H), 3.50 (m, 1H), 3.37 (m, 1H), 3.28 (m, 1H), 3.16 (t, J=4.9 Hz, 4H), 2.70-2.50 (m, 6H), 2.36-2.25 (m, 5H), 2.10-1.98 (m, 2H), 1.98-1.65 (m, 5H), 1.23-1.11 (m, 2H), 1.07-0.95 (m, 2H); MS (LC/MS, M+H⁺): 462

Example 45: Preparation of 3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-8-((3,3,3-trifluoropropyl)sulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 3,3,3-trifluoropropane-1-sulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 6.95 (d, J=8.3 Hz, 2H), 6.72 (d, J=8.5 Hz, 2H), 4.49 (m, 1H), 3.64 (m, 1H), 3.38-3.27 (m, 2H), 3.23 (m, 1H), 3.09-2.93 (m, 6H), 2.59-2.36 (m, 8H), 2.17 (dd, J=5.9, 13.0 Hz, 1H), 2.15 (s, 3H), 1.96-1.85 (m, 2H), 1.85-1.56 (m, 5H); MS (LC/MS, M+H⁺): 518

Example 46: Preparation of 8-(isobutylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except isobutanesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): NMR (400 MHz, CDCl₃) δ 7.08 (d, J=8.3 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 4.61 (m, 1H), 3.70 (m, 1H), 3.45-3.33 (m, 2H), 3.29 (m, 1H) 3.16 (t, J=4.8 Hz, 4H), 2.79 (dd, J=2.2, 6.6 Hz, 2H), 2.70-2.49 (m, 6H), 2.37-2.20 (m, 5H), 2.07-1.97 (m, 2H), 1.97-1.67 (m, 5H), 1.12 (d, J=6.7 Hz, 6H); MS (LC/MS, M+H⁺): 478

Example 47: Preparation of 8-(cyclopentylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except cyclopentanesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 6.95 (d, J=8.3 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 4.47 (m, 1H), 3.64 (m, 1H), 3.42-3.22 (m, 3H), 3.18 (m, 1H) 3.03 (t, J=4.9 Hz, 4H), 2.57-2.37 (m, 6H), 2.18 (dd, J=6.1, 12.9 Hz, 1H), 2.15 (s, 3H), 1.95-1.42 (m, 15H); MS (LC/MS, M+H⁺): 490

Example 48: Preparation of 8-(cyclohexylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except cyclohexanesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 6.95 (d, J=8.3 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 4.47 (m, 1H), 3.66 (m, 1H), 3.38 (m, 1H), 3.27 (m, 1H), 3.18 (m, 1H), 3.03 (t, J=4.9 Hz, 4H), 2.77 (tt, J=3.4, 12.0 Hz, 1H), 2.59-2.36 (m, 6H), 2.19 (dd, J=6.0, 12.9 Hz, 1H), 2.15 (s, 3H), 2.06-1.94 (b, 2H), 1.91-1.72 (m, 6H), 1.72-1.49 (m, 4H), 1.37 (qd, J=3.3, 12.3 Hz, 2H), 1.23-0.99 (m, 3H); MS (LC/MS, M+H⁺): 504

Example 49: Preparation of 8-(ethylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except ethanesulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 7.08 (d, J=8.2 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.61 (m, 1H), 3.75 (m, 1H), 3.51-3.35 (m, 2H), 3.30 (m, 1H), 3.15 (t, J=4.9 Hz, 4H), 2.98 (q, J=7.4 Hz, 2H), 2.70-2.48 (m, 6H), 2.31 (dd, J=6.2, 13.0 Hz, 1H), 2.28 (s, 3H), 2.07-1.96 (m, 2H), 1.96-1.66 (m, 5), 1.38 (t, J=7.4 Hz, 3H); MS (LC/MS, M+H⁺): 450

Example 50: Preparation of 8-(pyridin-3-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except pyridine-3-sulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): ¹H NMR (400 MHz, CDCl₃) δ 9.00 (d, J=2.3 Hz, 1H), 8.84 (dd, J=1.5, 4.8 Hz, 1H), 8.06 (dt, J=1.9, 8.0 Hz, 1H), 7.5 (dd, J=4.9, 7.9 Hz, 1H), 7.08 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.5 Hz, 2H), 4.55 (m, 1H), 3.56 (m, 1H), 3.29 (m, 1H), 3.24-3.05 (m, 6H), 2.66-2.47 (m, 6H), 2.27 (s, 3H) 2.09 (dd, J=6.0, 13.0 Hz, 1H), 2.09-1.96 (m, 2H), 1.96-1.64 (m, 5H); MS (LC/MS, M+H⁺): 499

Example 51: Preparation of 8-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 1-methyl-1H-pyrazole-4-sulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): NMR (400 MHz, CDCl₃) δ 7.75 (s, 1H), 7.71 (s, 1H), 7.07 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 4.55 (m, 1H), 3.95 (s, 3H), 3.48 (m, 1H), 3.23 (m, 1H), 3.13 (t, J=4.9 Hz, 4H), 3.02 (m, 1H), 2.93 (m, 1H), 2.67-2.48 (m, 6H), 2.27 (s, 3H), 2.22 (dd, J=6.1, 12.9 Hz, 1H), 2.11-1.96 (m, 2H), 1.96-1.64 (m, 5H); MS (LC/MS, M+H⁺): 502

Example 52: Preparation of 8-((1H-imidazol-4-yl)sulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except 1H-imidazole-4-sulfonyl chloride was substituted for methanesulfonyl chloride: ¹H NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.74 (s, 1H), 7.09 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 4.58 (b, 1H), 3.67 (m, 1H), 3.53 (m, 1H), 3.40-3.05 (m, 10H), 2.99 (m, 1H), 2.85 (m, 1H), 2.38 (dd, J=5.7, 12.9 Hz, 1H), 2.26 (s, 3H), 2.19-1.91 (m, 3H), 1.90-1.72 (m, 3H), 1.72-1.58 (m, 1H); MS (LC/MS, M+H⁺): 488

Example 53: Preparation of 8-(furan-2-ylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for 8-(methylsulfonyl)-3-(2-(4-(p-tolyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one formate, except furan-2-sulfonyl chloride was substituted for methanesulfonyl chloride and the title compound was purified by column chromatography on a silica gel column. (MeOH/DCM, 0%˜10%): NMR (400 MHz, CDCl₃) δ 7.59 (s, 1H), 7.07 (d, J=8.4 Hz, 2H), 7.02 (d, J=3.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 2H), 6.52 (dd, J=1.7, 3.3 Hz, 1H), 4.56 (m, 1H), 3.70 (m, 1H), 3.47 (m, 1H), 3.24 (m, 1H), 3.19-3.07 (m, 5H), 2.68-2.46 (m, 6H), 2.33-2.18 (m, 4H), 2.07-1.79 (m, 4H), 1.79-1.60 (m, 3H); MS (LC/MS, M+H⁺): 488

Example 54: Preparation of 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: A mixture of 8-benzyl-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one (3.25 g, 8.04 mmol, 1 eq.), Pd/C (0.65 g, 20% wt) and MeOH (54 mL) was stirred at RT under 1 atm of H₂ (filled balloon) overnight. The mixture was filtered through a plug of Celite, washed with MeOH (50 mL) and concentrated in vacuo to give a crude oil. The crude oil (2.43 g) was dissolved in dichloromethane (50 mL), followed by addition of triethylamine (5.55 mL, 38.8 mmol, 5 eq.). Cooled to 0° C. before the addition of methanesulfonyl chloride (2.83 g, 13.0 mmol, 1.1 eq.). The reaction was allowed to warm to RT and stir for 30 min. At this point the reaction was diluted with D.I. water and then extracted with dichloromethane (3×50 mL), the combined organic phase was dried over Na₂SO₄ and concentrated in vacuo to give a crude product which was further purified by column chromatography (EtOAc/DCM, 0%˜10%). ¹H NMR (400 MHz, CDCl₃) δ 4.61 (m, 1H), 3.75-3.65 (m, 2H), 3.60 (m, 1H), 3.37-3.18 (m, 3H), 2.75 (s, 3H), 2.21 (dd, J=6.0, 13.0 Hz, 1H), 2.02-1.91 (m, 2H), 1.91-1.62 (m, 5H), 0.83 (s, 9H), 0.00 (s, 6H).

Example 55: Preparation of 3-(2-hydroxyethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for tert-butyl 3-(2-hydroxyethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one was substituted for tert-butyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate and the product was initially purified by column chromatography on a C18 column. (ACN/H₂O, 0%˜100%, w/0.1% formic acid), followed by purification on a silica gel column (MeOH/DCM, 0%˜10%). ¹H NMR (400 MHz, CDCl₃) δ 4.73 (m, 1H), 3.84 (t, J=5.5 Hz, 2H), 3.68 (m, 1H), 3.41-3.32 (m, 2H), 3.29 (m, 1H), 2.83 (s, 3H), 2.33 (dd, J=6.0, 13.0 Hz, 1H), 2.10-2.00 (m, 2H), 2.10-1.71 (m, 6H).

Example 56: Preparation of 3-(2-bromoethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: A solution of 3-(2-hydroxyethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one (0.890 g, 3.21 mmol, 1 eq.) and dichloromethane (12 mL) was cooled to 0° C. before triphenylphosphine (1.26 g. 4.81 mmol, 1.5 eq.) and carbon tetrabromide (1.6 g, 4.81 mmol, 1.5 eq.) were sequentially added to the solution. The reaction solution was allowed to warm to RT and for 4 hrs. The resulting mixture was then filtered and concentrated in vacuo to give a crude mixture. This mixture was suspended in diethyl ether (50 mL) and filtered 2× using diethyl ether to wash the filter cakes. The final filtrate was loaded onto Celite in vacuo and further purified by column chromatography (EtOAc/DCM, 0%˜40%). ¹H NMR (400 MHz, MeOD) δ 4.72 (m, 1H), 3.67 (m, 1H), 3.54 (dd, J=5.3, 7.6 Hz, 2H), 3.44-3.25 (m, 3H), 2.82 (s, 3H), 2.34 (dd, J=6.0, 12.9 Hz, 1H), 2.31-2.21 (m, 1H), 2.21-2.10 (m, 1H), 2.10-1.98 (m, 2H), 1.88-1.71 (m, 3H).

Example 57: Preparation of 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: A solution of 3-(2-bromoethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one (50 mg, 0.147 mmol, 1 eq.), 1-(4-methoxyphenyl)-piperazine (59.33 mg, 0.308 mmol, 2.1 eq.) and Acetonitrile (2 mL) was microwaved for 1 hour at 120° C. The solvent was then evaporated in vacuo and the product was suspended in 15 mL of saturated NaHCO₃ and extracted in dichloromethane (3×15 mL). The combined organic phase was dried over Na₂SO₄ and concentrated in vacuo to give a crude mixture that was then dissolved in dichloromethane and purified by column chromatography (methanol/dichloromethane, 0%˜10%). NMR (400 MHz, CDCl₃) δ 7.4 (d, J=9.2 Hz, 2H), 6.5 (d, J=9.2 Hz, 2H), 4.61 (m, 1H), 3.77 (s, 3H), 3.67 (m, 1H), 3.36 (m, 2H), 3.29 (m, 1H), 3.1 (t, J=7.1 Hz, 4H), 2.8 (s, 3H), 2.62 (m, 4H), 2.56 (t, J=7.1 Hz, 2H), 2.29 (dd, J=7.2, 6 Hz, 1H), 2.05 (m, 2H), 1.99-1.71 (m, 6H); MS (LC/MS, M+H⁺): 452.

Example 58: Preparation of 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The tittle compound was prepared and purified according to the procedure for 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one except that 1-(4-trifluoromethylphenyl)-piperazine was substituted for 1-(4-methoxyphenyl)-piperazine. NMR (400 MHz, CDCl₃) δ 7.5 (d, J=8.76 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 4.64 (m, 1H), 3.68 (m, 1H), 3.46-3.28 (m, 7H), 2.83 (s, 3H), 2.67-2.55 (m, 6H), 2.3 (dd, J=7.1, 6.1 Hz, 1H), 2.11-2.01 (m, 2H), 2.0-1.74 (m, 5H); MS (LC/MS, M+H⁺): 490

Example 59: Preparation of 4-(4-(2-(8-(methylsulfonyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-3-yl)ethyl)piperazin-1-yl)benzonitrile: The tittle compound was prepared and purified according to the procedure for 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one except that triethylamine (0.06 mL, 0.44 mmol, 3 eq.) was added in the microwave mixture and 1-(4-cyanophenyl)-piperazine was substituted for 1-(4-methoxyphenyl)-piperazine.: ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 4.61 (m, 1H), 3.65 (m, 1H), 3.43-3.26 (m, 7H), 2.81 (s, 3H), 2.64-2.52 (m, 6H), 2.28 (dd, J=6.8, 5.9 Hz, 1H), 2.02 (m, 2H), 1.96-1.74 (m, 5H); MS (LC/MS, M+H⁺): 447

Example 60: Preparation of 8-(methylsulfonyl)-3-(2-(4-(4-nitrophenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The tittle compound was prepared and purified according to the procedure for 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one except that it was microwaved for 1.5 hours at 120° C. and 1-(4-nitrophenyl)-piperazine was substituted for 1-(4-methoxyphenyl)-piperazine. ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=9.3 Hz, 2H), 6.82 (d, J=9.3 Hz, 2H), 4.62 (m, 1H), 3.66 (m, 1H), 3.46-3.36 (m, 4H), 3.36-3.28 (m, 3H), 2.8 (s, 3H), 2.67-2.5 (b, 6H), 2.28 (dd, J=6.8, 5.9 Hz, 1H), 2.08-1.98 (m, 2H), 1.95-1.72 (m, 5H); MS (LC/MS, M+H⁺): 467

Example 61: Preparation of 3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The tittle compound was prepared and purified according to the procedure for 3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one except that it was microwaved for 2 hours at 120° C. and 1-(4-chlorophenyl)-piperazine was substituted for 1-(4-methoxyphenyl)-piperazine. NMR (400 MHz, CDCl₃) δ 7.19 (d, J=8.9 Hz, 2H), 6.82 (d, J=8.9 Hz, 2H), 4.6 (m, 1H), 3.65 (m, 1H), 3.42-3.26 (m, 3H), 3.15 (t, J=4.9 Hz, 4H), 2.8 (s, 3H), 2.66-2.52 (m, 6H), 2.27 (dd, J=6.8, 5.9 Hz, 1H), 2.07-1.98 (m, 2H), 1.97-1.7 (m, 5H); MS (LC/MS, M+H⁺): 456

Example 62: Preparation of 3-(2-(4-(4-iodophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The tittle compound was prepared and purified according to the procedure for 3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one except that and 1-(4-iodophenyl)-piperazine was substituted for 1-(4-methoxyphenyl)-piperazine. ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J=8.8 Hz, 2H), 6.65 (d, J=8.8 Hz, 2H), 4.58 (m, 1H), 3.64 (m, 1H), 3.4-3.24 (m, 3H), 3.15 (t, J=4.8 Hz, 4H), 2.79 (s, 3H), 2.62-2.5 (m, 6H), 2.26 (dd, J=6.8, 6 Hz, 1H), 2.0-1.96 (m, 2H), 1.95-1.69 (m, 5H); MS (LC/MS, M+H⁺): 548

Example 63: Preparation of 3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The tittle compound was prepared and purified according to the procedure for 3-(2-(4-(4-chlorophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one except that and 1-(4-fluorophenyl)-piperazine was substituted for 1-(4-methoxyphenyl)-piperazine. ¹H NMR (400 MHz, CDCl₃) δ 6.94 (m, 2H), 6.85 (m, 2H), 4.59 (m, 1H), 3.65 (m, 1H), 3.4-3.24 (m, 3H), 3.1 (t, J=4.8 Hz, 4H), 2.8 (s, 3H), 2.65-2.5 (m, 6H), 2.27 (dd, J=6.7, 5.9 Hz, 1H), 2.0 (m, 2H), 1.97-1.69 (m, 5H); MS (LC/MS, M+H⁺): 440.

Preparation of 3-morpholino-4-nitrobenzonitrile: A solution of 3-fluoro-4-nitrobenzonitrile (0.6 g, 3.61 mmol, 1 eq.) and morpholine (0.629 g, 7.22 mmol, 2 eq.) in dimethyl sulfoxide (6.57 mL) was heated at 60° C. for 4 hours. The reaction solution was diluted with water 20 mL and extracted with ethyl acetate (3×20 mL). The combined organic phase was dried over Na₂SO₄ and concentrated in vacuo to give a crude product which was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J=8.3 Hz, 1H), 7.40 (d, J=1.5 Hz, 1H), 7.33 (dd, J=1.6, 8.3 Hz, 1H), 3.86 (m, 4H), 3.11 (m, 4H); MS (LC/MS, M+H⁺): 234

Preparation of 4-(5-methyl-2-nitrophenyl)morpholine: The title compound was prepared according to the procedure for 3-morpholino-4-nitrobenzonitrile, except 2-fluoro-4-methyl-1-nitrobenzene was substituted for 3-fluoro-4-nitrobenzonitrile. NMR (400 MHz, CDCl₃) δ 7.76 (d, J=8.2 Hz, 1H), 6.93 (b, 1H), 6.88 (d, J=8.3 Hz, 1H), 3.86 (m, 4H), 3.06 (m, 4H), 2.40 (s, 3H); MS (LC/MS, M+H⁺): 223

Preparation of 3-morpholino-4-nitrophenol: The title compound was prepared according to the procedure for 3-morpholino-4-nitrobenzonitrile, except 3-fluoro-4-nitrophenol was substituted for 3-fluoro-4-nitrobenzonitrile. NMR (400 MHz, MeOD) δ 7.90 (d, J=9.0 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 6.49 (dd, J=2.5, 9.0 Hz, 1H), 3.83 (m, 4H), 3.02 (m, 4H); MS (LC/MS, M+H⁺): 225

Preparation of 4-(2-nitro-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)morpholine: A solution of 3-morpholino-4-nitrophenol (1.34 g, 5.98 mmol, 1 eq.), 2-(trimethylsilyl)ethoxymethyl chloride (1.05 g, 6.28 mmol, 1.05 eq.) and N,N-diisopropylethylamine (2.31 g, 17.9 mmol, 3 eq.) in dichloromethane (30.0 mL) was stirred at 25° C. for 16 hours. The reaction solution was diluted with 40 mL of water and extracted with dichloromethane (3×40 mL). The combined organic phase was dried over Na₂SO₄ and concentrated in vacuo to give a crude product which was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J=9.7 Hz, 1H), 6.68 (m, 2H), 5.24 (s, 2H), 3.85 (m, 4H), 3.74 (m, 2H), 3.04 (m, 4H), 0.94 (m, 2H), 0.00 (s, 9H); MS (LC/MS, M+H⁺): 355

Preparation of 4-(5-methyl-2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine: A mixture of 4-(5-methyl-2-nitrophenyl)morpholine (1.58 g, 7.11 mmol, 1 eq.), Pd on carbon (316 mg, 20% wt) and methanol (72 mL) was stirred at 25° C. under 1 atm of H₂ (filled balloon) for 48 hours. The mixture was filtered through a plug of Celite, washed with methanol (50 mL) and concentrated in vacuo to give the crude intermediate, 4-methyl-2-morpholinoaniline.

(((4-nitrophenyl)sulfonyl)azanediyl)bis(ethane-2,1-diyl)bis(4-nitrobenzenesulfonate) (1.0 g, 1.5 mmol, 1 eq.), 4-methyl-2-morpholinoaniline (0.346 g, 1.8 mmol, 1.2 eq.), N,N-diisopropylethylamine (1.55 g, 12.0 mmol, 4 eq.) and acetonitrile (4.7 mL) were mixed in a microwave reaction vial (10 mL) fitted with a no-invasive vial cap. The reaction vials containing the mixture were reacted in the microwave for 1 h at 175° C. After 1 h, the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with HCl (10%, 3×30 mL) and saturated NaHCO₃ (40 mL). The organic phase was dried over Na₂SO₄ and concentrated in vacuo to afford the crude product. The title compound was purified by column chromatography on a silica gel column. (ethyl acetate/dichloromethane, 0%˜10%): NMR (400 MHz, CDCl₃) δ 8.44 (d, J=8.9 Hz, 2H), 8.02 (d, J=9.0 Hz, 2H), 6.82 (m, 2H), 6.74 (b, 1H), 3.71 (t, J=4.2 Hz, 4H), 3.24 (b, 8H), 3.05 (m, 4H), 2.29 (s, 3H); MS (LC/MS, M+H⁺): 447

Preparation of 3-morpholino-4-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)benzonitrile: The title compound was prepared according to the procedure for 4-(5-methyl-2-(4((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine, except 3-morpholino-4-nitrobenzonitrile was substituted for 4-(5-methyl-2-nitrophenyl)morpholine and 4-amino-3-morpholinobenzonitrile for 4-methyl-2-morpholinoaniline NMR (400 MHz, CDCl₃) δ 8.43 (d, J=8.8 Hz, 2H), 8.01 (d, J=8.8 Hz, 2H), 7.30 (dd, J=1.8, 8.2 Hz, 1H), 7.14 (d, J=1.8 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 3.73 (t, J=4.5 Hz, 4H), 3.36 (m, 4H), 3.26 (m, 4H), 3.02 (t, J=4.3 Hz, 4H); MS (LC/MS, M+H⁺): 458

Preparation of 4-(2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)morpholine: The title compound was prepared according to the procedure for 4-(5-methyl-2-(4((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine, except 4-(2-nitro-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)morpholine was substituted for 4-(5-methyl-2-nitrophenyl)morpholine and 2-morpholino-4-((2-(trimethylsilyl)ethoxy)methoxy)aniline for 4-methyl-2-morpholinoaniline ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J=8.8 Hz, 2H), 8.01 (d, J=8.7 Hz, 2H), 6.80 (d, J=8.7 Hz, 1H), 6.67 (dd, J=2.7, 8.7 Hz, 1H), 6.60 (d, J=2.6 Hz, 1H), 5.14 (s, 2H), 3.74 (m, 2H). 3.68 (t, J=4.4 Hz, 4H), 3.23 (b, 4H), 3.16 (b, 4H), 3.03 (b, 4H), 0.95 (m, 2H), 0.00 (s, 9H); MS (LC/MS, M+H⁺): 579

Preparation of 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine: Potassium carbonate (1.5 g, 10.8 mmol 12 eq.) was added to a mixture of acetonitrile and dimethylsulfoxide (CH₃CN/DMSO 49:1, 2.4 mL) and heated to 50° C. Thiophenol (0.988 g, 8.96 mmol, 10 eq.) was added dropwise via syringe to the mixture with stirring. After 30 minutes a solution of 4-(5-methyl-2-(4((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine (0.410 g, 0.896 mmol, 1 eq.) in acetonitrile and dimethyl sulfoxide (acetonitrile/dimethyl sulfoxide 49:1, 4.5 mL) was added dropwise. The reaction mixture was stirred for 3 hours, quenched with excess NaOH solution (40%) and concentrated under reduced pressure. The residue was extracted with dichloromethane (5×30 mL) and the organic phase was dried over MgSO₄, and concentrated in vacuo to give a crude oil. The oil was purified by reverse phase chromatography (acetonitrile in H₂O, gradient from 1%-100% with 0.1% formic acid) to afford the formic acid salt of the desired piperazine. The salt was dissolved in dichloromethane, washed with saturated NaHCO₃ solution, and the organic phase concentrated in vacuo to provide the product. ¹H NMR (400 MHz, CDCl₃) δ 6.87-6.76 (m, 2H), 6.71 (s, 1H), 3.84 (t, J=4.5 Hz, 4H), 3.18 (b, 4H), 3.07 (b, 4H), 2.98 (b, 4H), 2.29 (s, 3H); MS (LC/MS, M+H⁺): 262

Preparation of 3-morpholino-4-(piperazin-1-yl)benzonitrile: The title compound was prepared according to the procedure for 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine, except 3-morpholino-4-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)benzonitrile was substituted for 4-(5-methyl-2-(4((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine. NMR (400 MHz, CDCl₃) δ 7.24 (dd, J=1.8, 8.2 Hz, 1H), 7.08 (d, J=1.8 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 3.81 (t, J=4.6 Hz, 4H), 3.21 (b, 4H), 3.11 (b, 4H), 3.00 (b, 4H); MS (LC/MS, M+H⁺): 273

Preparation of 4-(2-(piperazin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy) phenyl)morpholine: The title compound was prepared according to the procedure for 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine, except 4-(2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)morpholine was substituted for 4-(5-methyl-2-(4-((4-nitrophenyl)sulfonyl)piperazin-1-yl)phenyl)morpholine. ¹H NMR (400 MHz, CDCl₃) δ 6.83 (d, J=8.6 Hz, 1H), 6.67 (dd, J=2.7, 8.5 Hz, 1H), 6.59 (d, J=2.8 Hz, 1H), 3.82 (t, J=4.7 Hz, 4H), 3.74 (m, 2H), 3.18 (b, 4H), 3.10-2.92 (b, 8H), 0.95 (m, 2H), 0.00 (s, 9H); MS (LC/MS, M+H⁺): 394

Preparation of tert-butyl 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: A solution of tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.05 g, 0.138 mmol, 1 eq.), 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine (0.044 g, 0.166 mmol, 1.2 eq.), and triethylamine (0.070 g, 0.69 mmol, 5 eq.) in acetonitrile (2 mL) was microwaved at 120° C. for 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a crude product. The title compound was purified by column chromatography on a silica gel column (methanol/dichloromethane, 0%˜10%) ¹H NMR (400 MHz, CDCl₃) δ 6.87-6.76 (m, 2H), 6.71 (s, 1H), 4.59 (m, 1H), 3.98 (m, 1H), 3.90-3.73 (m, 5H), 3.31-2.94 (m, 10H), 2.70-2.47 (m, 6H), 2.39 (dd, J=6.2, 12.8 Hz, 1H), 2.28 (s, 3H), 2.03-1.70 (m, 5H), 1.60 (m, 1H), 1.55-1.38 (m, 10H); MS (LC/MS, M+H⁺): 543

Preparation of tert-butyl 3-(2-(4-(4-cyano-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate: The title compound was prepared according to the procedure for tert-butyl 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except 3-morpholino-4-(piperazin-1-yl)benzonitrile was substituted for 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine. ¹H NMR (400 MHz, CDCl₃) δ 7.26 (dd, J=1.8, 8.3 Hz, 1H), 7.09 (d, J=1.6 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 4.57 (m, 1H), 3.96 (m, 1H), 3.89-3.73 (m, 5H), 3.40-2.98 (m, 10H), 2.72-2.45 (m, 6H), 2.37 (dd, J=6.1, 12.8 Hz, 1H), 2.03-1.67 (m, 5H), 1.58 (m, 1H), 1.54-1.38 (m, 10H); MS (LC/MS, M+H⁺): 554

Preparation of 8-(methylsulfonyl)-3-(2-(4-(2-morpholino-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro[4.5]decan-1-one: The title compound was prepared according to the procedure for tert-butyl 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, except 4-(2-(piperazin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)morpholine was substituted for 4-(5-methyl-2-(piperazin-1-yl)phenyl)morpholine and 3-(2-bromoethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one for tert-butyl 3-(2-bromoethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate. NMR (400 MHz, CDCl₃) δ 6.83 (d, J=8.6 Hz, 1H), 6.66 (dd, J=2.7, 8.6 Hz, 1H), 6.59 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 4.61 (m, 1H), 3.81 (t, J=4.4 Hz, 4H), 3.74 (m, 2H), 3.66 (m, 1H), 3.35 (m, 2H), 3.26 (m, 1H), 3.21-2.94 (b, 8H), 2.80 (s, 3H), 2.70-2.41 (m, 6H), 2.30 (dd, J=5.6, 12.9 Hz, 1H), 2.08-1.67 (m, 7H), 0.95 (m, 2H), 0.00 (s, 9H); MS (LC/MS, M+H⁺): 653

Preparation of 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: A solution of tert-butyl 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.077 g, 0.142 mmol, 1 eq.) in trifluoroacetic acid:dichlroromethane (1:3, 2 mL) was allowed to stir at 25° C. for 30 minutes. The reaction solution was diluted with methanol (2 mL) and concentrated in vacuo to give a crude intermediate as a trifluoroacetic acid salt. The resulting material was dissolved in dichloromethane (10 mL) and washed with sat. NaHCO₃ (aq.) solution (10 mL). The aqueous layer was backwashed with dichloromethane (2×10 mL) and the combined organic layers were dried over Na₂SO₄ and concentrated in vacuo to give a crude intermediate as a free base.

The resulting free base (0.052 g, 0.114 mmol, 1 eq.) was dissolved in dichloromethane (2 mL) and cooled to 0° C., and trimethylamine (0.058 g, 0.57 mmol, 5 eq.) and methanesulfonyl chloride (0.026, 0.228 mmol, 2 eq.) were added. The reaction solution was allowed to stir at 25° C. for 30 minutes and then concentrated in vacuo to give a crude solid. The title compound was purified by column chromatography on a silica gel column. (methanol/dichloromethane, 0%˜10%) ¹H NMR (400 MHz, CDCl₃) δ 6.79-6.68 (m, 2H), 6.64 (s, 1H), 4.54 (m, 1H), 3.75 (t, J=4.4 Hz, 4H), 3.59 (m, 1H), 3.37-2.88 (b, 11H), 2.74 (s, 3H), 2.69-2.33 (b, 6H), 2.27-2.16 (m, 4H), 2.02-1.92 (m, 2H), 1.92-1.62 (m, 5H); MS (LC/MS, M+H⁺): 521

Preparation of 4-(4-(2-(8-(methylsulfonyl)-1-oxo-2-oxa-8-azaspiro[4.5]decan-3-yl)ethyl)piperazin-1-yl)-3-morpholinobenzonitrile: The title compound was prepared according to the procedure for 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one, except tert-butyl 3-(2-(4-(4-cyano-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was substituted for 3-(2-(4-(4-methyl-2-morpholinophenyl)piperazin-1-yl)ethyl)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate. ¹H NMR (400 MHz, CDCl₃) δ 7.29 (dd, J=1.8, 8.3 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 4.63 (m, 1H), 3.85 (t, J=4.3 Hz, 4H), 3.67 (m, 1H), 3.55-2.96 (b, 11H), 2.83 (s, 3H), 2.75-2.40 (b, 6H), 2.30 (dd, J=6.0, 12.9 Hz, 1H), 2.12-1.99 (m, 2H), 1.99-1.71 (m, 5H); MS (LC/MS, M+H⁺): 532

Preparation of 3-(2-(4-(4-hydroxy-2-morpholinophenyl)piperazin-1-yl)ethyl)-8-(methylsulfonyl)-2-oxa-8-azaspiro[4.5]decan-1-one: To a small vial, 8-(methylsulfonyl)-3-(2-(4-(2-morpholino-4((2-(trimethylsilyl)ethoxy)methoxy)phenyl)piperazin-1-yl)ethyl)-2-oxa-8-azaspiro [4.5]decan-1-one (0.190 g, 0.291 mmol, 1 eq.) was added and dissolved in hexamethylphosphoramide (1.5 mL). Tetra-n-butylammonium fluoride trihydrate (0.230 g, 0.873 mmol, 3 eq.) was added, followed by 300 mg of 4 Å molecular sieves. The reaction mixture was stirred at 60° C. for 48 hours before being filtered and concentrated in vacuo to give a crude oil. The title compound was purified by column chromatography on a silica gel column. (methanol/dichloromethane, 0%˜10%) ¹H NMR (400 MHz, CDCl₃) δ 6.70 (d, J=9.2 Hz, 1H), 6.40-6.32 (m, 2H), 4.53 (m, 1H), 3.75 (t, J=4.3 Hz, 4H), 3.58 (m, 1H), 3.38-2.84 (b, 11H), 2.74 (s, 3H), 2.70-2.33 (b, 6H), 2.21 (dd, J=5.9, 12.8 Hz, 1H), 2.01-1.80 (m, 4H), 1.79-1.60 (m, 3H); MS (LC/MS, M+H⁺): 523.

Formulations

The present invention also relates to compositions or formulations which comprise the 5-hydroxytryptamine receptor 7 activity modulators according to the present invention. In general, the compositions of the present invention comprise an effective amount of one or more compounds of the disclosure and salts thereof according to the present invention which are effective for providing modulation of 5-hydroxytryptamine receptor 7 activity; and one or more excipients.

For the purposes of the present invention the term “excipient” and “carrier” are used interchangeably throughout the description of the present invention and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”

The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.

The present teachings also provide pharmaceutical compositions that include at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. The compounds can be formulated in conventional manner, for example, in a manner similar to that used for known 5-hydroxytryptamine receptor 7 activity modulators. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99% of the compound.

Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form can contain from about 1 mg/kg of compound to about 500 mg/kg of compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.

In some cases it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.]

Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

To increase the effectiveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For example, other active compounds (i.e., other active ingredients or agents) effective in treating the target disease can be administered with compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein.

Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human subject. The present teachings accordingly provide methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings including its pharmaceutically acceptable salt) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with pharmaceutically acceptable carriers. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder.

Non-limiting examples of compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more compounds of the disclosure according to the present invention and one or more excipients; from about 0.01 mg to about 100 mg of one or more compounds of the disclosure according to the present invention and one or more excipients; and from about 0.1 mg to about 10 mg of one or more compounds of the disclosure according to the present invention; and one or more excipients.

Procedures

The following procedures can be utilized in evaluating and selecting compounds as 5-hydroxytryptamine receptor 7 activity modulators.

Radiolabel Binding Studies for Serotonin 5HT7 Receptors, Method 1:

A solution of the compound of the disclosure to be tested is prepared as a 1-mg/ml stock in Assay Buffer or DMSO according to its solubility. A similar stock of the reference compound chlorpromazine is also prepared as a positive control. Eleven dilutions (5× assay concentration) of the compound of the disclosure and chlorpromazine are prepared in the Assay Buffer by serial dilution to yield final corresponding assay concentrations ranging from 10 pM to 10 μM.

A stock concentration of 5 nM [³H]LSD (lysergic acid diethyl amide) is prepared in 50 mM Tris-HCl, 10 mM MgCl₂, 1 mM EDTA, pH 7.4 (Assay Buffer). Aliquots (50 μl) of radioligand are dispensed into the wells of a 96-well plate containing 100 μl of Assay Buffer. Duplicate 50-μl aliquots of the compound of the disclosure test and chlorpromazine positive control reference compound serial dilutions are added.

Membrane fractions of cells expressing recombinant 5HT₇ receptors (50 μL) are dispensed into each well. The membranes are prepared from stably transfected cell lines expressing 5HT₇ receptors cultured on 10-cm plates by harvesting PBS-rinsed monolayers, resuspending and lysing in chilled, hypotonic 50 mM Tris-HCl, pH 7.4, centrifuging at 20,000×g, decanting the supernatant and storing at −80° C.; the membrane preparations are resuspended in 3 ml of chilled Assay Buffer and homogenized by several passages through a 26 gauge needle before using in the assay.

The 250-μl reactions are incubated at room temperature for 1.5 hours, then harvested by rapid filtration onto 0.3% polyethyleneimine-treated, 96-well filter mats using a 96-well Filtermate harvester. Four rapid 500-μl washes are performed with chilled Assay Buffer to reduce non-specific binding. The filter mats are dried, then scintillant is added to the filters and the radioactivity retained on the filters is counted in a Microbeta scintillation counter.

Raw data (dpm) representing total radioligand binding (i.e., specific+non-specific binding) are plotted as a function of the logarithm of the molar concentration of the competitor (i.e., test or reference compound). Non-linear regression of the normalized (i.e., percent radioligand binding compared to that observed in the absence of test or reference compound) raw data is performed in Prism 4.0 (GraphPad Software) using the built-in three parameter logistic model describing ligand competition binding to radioligand-labeled sites: y=bottom+[(top−bottom)/(1+10x−log IC ₅₀)] where bottom equals the residual radioligand binding measured in the presence of 10 μM reference compound (i.e., non-specific binding) and top equals the total radioligand binding observed in the absence of competitor. The log IC₅₀ (i.e., the log of the ligand concentration that reduces radioligand binding by 50%) is thus estimated from the data and used to obtain the Ki by applying the Cheng-Prusoff approximation: Ki=IC ₅₀/(1+[ligand]/KD) where [ligand] equals the assay radioligand concentration and KD equals the affinity constant of the radioligand for the target receptor.

Compounds of the disclosure are also screened at a single concentration of 10 μM using the same method described for the Radiolabel Binding Studies for Serotonin 5HT₇ receptors to determine the percent inhibition of [³H]LSD binding.

Radiolabel Binding Studies for Serotonin 5-HT7 Receptors, Method 2:

A solution of the compound of the disclosure to be tested is prepared as a 1-mg/ml stock in Assay Buffer or DMSO according to its solubility. A similar stock of the reference compound chlorpromazine is also prepared as a positive control. Eleven dilutions (5× assay concentration) of the compound of the disclosure and chlorpromazine are prepared in the Assay Buffer by serial dilution to yield final corresponding assay concentrations ranging from 10 pM to 10 μM.

A stock concentration of 5 nM [³H]-5-Hydroxytryptamine ([³H]-5HT) is prepared in 50 mM Tris-HCl, 10 mM MgCl₂, 1 mM EDTA, pH 7.4 (Assay Buffer). Aliquots (50 μl) of radioligand are dispensed into the wells of a 96-well plate containing 100 μl of Assay Buffer. Duplicate 50-μl aliquots of the compound of the disclosure test and chlorpromazine positive control reference compound serial dilutions are added.

Membrane fractions of cells expressing recombinant 5HT₇ receptors (50 μL) are dispensed into each well. The membranes are prepared from stably transfected cell lines expressing 5HT₇ receptors cultured on 10-cm plates by harvesting PBS-rinsed monolayers, resuspending and lysing in chilled, hypotonic 50 mM Tris-HCl, pH 7.4, centrifuging at 20,000×g, decanting the supernatant and storing at −80° C.; the membrane preparations are resuspended in 3 ml of chilled Assay Buffer and homogenized by several passages through a 26 gauge needle before using in the assay.

The 250-μl reactions are incubated at room temperature for 1.5 hours, then harvested by rapid filtration onto 0.3% polyethyleneimine-treated, 96-well filter mats using a 96-well Filtermate harvester. Four rapid 500-μl washes are performed with chilled Assay Buffer to reduce non-specific binding. The filter mats are dried, then scintillant is added to the filters and the radioactivity retained on the filters is counted in a Microbeta scintillation counter.

Raw data (dpm) representing total radioligand binding (i.e., specific+non-specific binding) are plotted as a function of the logarithm of the molar concentration of the competitor (i.e., test or reference compound). Non-linear regression of the normalized (i.e., percent radioligand binding compared to that observed in the absence of test or reference compound) raw data is performed in Prism 4.0 (GraphPad Software) using the built-in three parameter logistic model describing ligand competition binding to radioligand-labeled sites: y=bottom+[(top−bottom)/(1+10x−log IC ₅₀)] where bottom equals the residual radioligand binding measured in the presence of 10 μM reference compound (i.e., non-specific binding) and top equals the total radioligand binding observed in the absence of competitor. The log IC₅₀ (i.e., the log of the ligand concentration that reduces radioligand binding by 50%) is thus estimated from the data and used to obtain the Ki by applying the Cheng-Prusoff approximation: Ki=IC ₅₀/(1+[ligand]/KD) where [ligand] equals the assay radioligand concentration and KD equals the affinity constant of the radioligand for the target receptor.

Compounds of the disclosure are also screened at a single concentration of 10 μM using the same method described for the Radiolabel Binding Studies for Serotonin 5HT₇ receptors to determine the percent inhibition of [³H]-5HT binding.

Results for representative compounds according to the present invention are listed in Table 11.

TABLE 11 Radiolabel Binding Studies for Serotonin 5HT₇ receptors results for exemplary compounds of the disclosure 5-HT₇ 5-HT7 % inhib IC₅₀ Entry Structure @10 uM (nm)  1

96.5  18  2

88.8 149  3

90    81  4

88.5 122  5

91.6 102  6

90.5  93  7

N.D.  34  8

100  46  9

N.D. 303 10

N.D.  64 11

N.D.  77 12

N.D. 108 13

N.D.  96 14

N.D.  47 15

N.D. 131 16

N.D.  56 17

N.D. 116 18

N.D.  86 19

N.D. 461 20

N.D.  67 21

N.D.  75 22

N.D. 202 N.D. = not determined

Functional Serotonin 5HT₇ Assay, Method 1:

Cell lines stably expressing human 5HT₇ receptors are seeded in 96-well, poly-L-lysine-coated plates 48 hours prior to the assay (40,000 cells per well) in Dulbecco's Modified Eagle Medium (DMEM) containing 5% dialyzed serum. Twenty hours prior to the assay, the medium is changed to serum-free DMEM. On the day of the assay, the DMEM is washed and replaced with 30 μl of assay buffer (1× Krebs-Ringer bicarbonate glucose buffer, 0.75 mM IBMX, pH 7.4). A 10-min pre-incubation is performed in a 37-degree centigrade, humidified incubator. Then, the cells are stimulated by addition of 30 μl of 2× dilutions of compounds of the disclosure or chlorpromazine (final concentrations ranging from 0.1 nM to 10 μM, each concentration assayed in triplicate). A positive control (100 μM forskolin) is also included. Accumulation of cAMP is allowed to continue for 15 min, after which the buffer is removed and the cells are lysed with Cell Lysis Buffer (CatchPoint cAMP Assay Kit, Molecular Devices). Next, the lysates are transferred to 96-well, glass-bottom plates coated with goat anti-rabbit IgG and adsorbed with rabbit anti-cAMP (Molecular Devices). Following a 5 minute incubation, horseradish peroxidase-cAMP conjugate is added (Molecular Devices) and a 2-hour incubation is performed at room temperature. Then, after three washes with Wash Buffer (Molecular Devices), Stoplight Red substrate (Molecular Devices), reconstituted in Substrate Buffer (Molecular Devices) containing freshly-added 1 mM H₂O₂, is added and, after a 15-min incubation at room temperature, fluorescence is measured (excitation 510-545 nm, emission 565-625 nm). For each assay, a cAMP calibration curve is generated and controls without lysate and without antibody are included.

For agonist tests, raw data (maximum fluorescence, fluorescence units) for each concentration of the compounds of the disclosure or chlorpromazine are normalized to the basal (vehicle-stimulated) fluorescence (reported as fold increase over basal) and plotted as a function of the logarithm of the molar concentration of the drug (i.e., test or reference compound). Non-linear regression of the normalized data is performed in Prism 4.0 (GraphPad Software) using the built-in three parameter logistic model (i.e., sigmoidal concentration-response) describing agonist-stimulated activation of one receptor population: y=bottom+[(top−bottom)/(1+10x−log EC50)] where bottom equals the best-fit basal fluorescence and top equals the best-fit maximal fluorescence stimulated by the compound of the disclosure or chlorpromazine. The log EC₅₀ (i.e., the log of the drug concentration that increases fluorescence by 50% of the maximum fluorescence observed for the compound of the disclosure or chlorpromazine is thus estimated from the data, and the EC₅₀ (agonist potency) is obtained. To obtain an estimate of the relative efficacy of the test compound (Rel. Emax), its best-fit top is compared to and expressed as a ratio of that for the chlorpromazine (Rel. Emax of the reference agonist is 1.00).

To ascertain whether compounds of the disclosure are antagonists, a double-addition paradigm is employed. First, 30 μl of a compound of the disclosure (20 μM) is added (10 μM final concentration) and a 15 minute incubation is performed. Then, 30 μl of chlorpromazine (3×; EC₉₀) is added (final concentration of agonist is EC30) and cAMP accumulation is allowed to proceed for 15 minutes. The samples are then processed for cAMP measurements as detailed above. Measurements of chlorpromazine-induced cAMP accumulation are compared to the signals elicited by the chlorpromazine following addition of vehicle instead of test compound and expressed as a ratio. ‘Hits’ (compounds that antagonize chlorpromazine-stimulated increases in baseline-normalized fluorescence by at least 50%) are then characterized by a modified Schild analysis.

For modified Schild analysis, a family of chlorpromazine concentration-response isotherms is generated in the absence and presence of graded concentrations of test compound (added 15 min prior to reference agonist). Theoretically, compounds that are competitive antagonists cause a dextral shift of agonist concentration-response isotherms without reducing the maximum response to agonist (i.e., surmountable antagonism). However, on occasion, factors such as non-competitive antagonism, hemiequilibria, and/or receptor reserve cause apparent insurmountable antagonism. To account for such deviations, we apply the modified Lew-Angus method to ascertain antagonist potency (Christopoulos et al., 1999). Briefly, equieffective concentrations of agonist (concentrations of agonist that elicit a response equal to the EC25% of the agonist control curve) are plotted as a function of the compound of the disclosure concentration present in the wells in which they were measured. Non-linear regression of the baseline-normalized data is performed in Prism 4.0 using the following equation: pEC25%=−log([B]+10−pK)−log c where EC25% equals the concentration of agonist that elicits a response equal to 25% of the maximum agonist control curve response and [B] equals the antagonist concentration; K, c, and s are fit parameters. The parameter s is equal to the Schild slope factor. If s is not significantly different from unity, pK equals pKB; otherwise, pA2 is calculated (pA2=pK/s). The parameter c equals the ratio EC_(25%)/[B].

Functional Efficacy Assay for 5-HT₇ Receptors Method 2:

Functional efficacy of the compounds of the disclosure on 5-HT₇ serotonin receptors were measured in a cell based cAMP enzyme fragment complementation assay using the HitHunter cAMP assay (DiscoveRx). Cells stably expressing human 5HT₇ receptors were plated in 96-well plates at 4000 cells/well, 16-20 hours prior to assay in growth media (Ultraculture medium, 2 mM GlutaMax and G418 1 mg/mL. Serial dilutions of the agonist, 5-Carboxamidotryptamine (5-CT), were prepared in a final concentration range of 10 μM to 10 nM. Compounds of the disclosure were prepared in 3-fold serial dilutions to obtain a final concentration range of 1004 to 0.1 nM. Compounds of the disclosure are tested for agonist activity in the absence of 5-CT and antagonist activity in the presence of 5-CT. For the cAMP assay, the protocol was followed according to the instructions provided by the supplier. Briefly, cells were incubated with a compound of the disclosure for 30 minutes at 37° C. prior to addition of EC70 concentration of 5-CT. After an additional 30 minutes, cAMP antibody/cell lysis solution was added (20 μL/well) and incubated for 60 minutes at room temperature. cAMP XS+EA reagent is added (20 μL/well) and incubated for 2 hours at room temperature. Luminescence was read on the Envision Multilabel plate reader.

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.

While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations. 

What is claimed is:
 1. A compound having formula (XXV):

or a pharmaceutically acceptable salt thereof, wherein: R^(2d) is selected from the group consisting of C₁₋₆ linear alkyl, —(CH₂)_(q)CN, —(CH₂)_(q)SO₂R¹³,

R^(1a), R^(1b), R^(1c), R^(1d), and R^(1c) are at each occurrence independently selected from the group consisting of H, halogen, CN, C₁₋₆ linear alkyl, and C₁₋₆ linear alkoxy; R³ is selected from a group consisting of optionally substituted phenyl or

R¹³ is C₁₋₆ linear alkyl; and q is 1, 2, or
 3. 2. The compound of claim 1, wherein R²d is


3. The compound of claim 1, wherein R^(2d) is C₁₋₆ linear alkyl.
 4. The compound of claim 1, wherein R^(2d) is selected from the group consisting of methyl, unsubstituted phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-cyanophenyl, —(CH₂)CN, —(CH₂)SO₂Me,


5. The compound of claim 1, wherein R³ is selected from the group consisting of phenyl, 4-Me-phenyl, 2-morpholino-phenyl, 4-Cl-phenyl, 4-cyano-2-morpholino-phenyl, 4-methyl-2-morpholino-phenyl, 4-hydroxy-2-morpholino-phenyl, 4-OH-phenyl, and 2-methyl-1H-benzo[d]imidazol-4-yl.
 6. The compound of claim 1, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 7. A composition comprising an effective amount of at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof.
 8. The composition according to claim 7, further comprising at least one excipient.
 9. A method of treating a disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity, said method comprising administering to a subject an effective amount of at least one compound according to the claim 1 to treat the disease.
 10. The method of claim 9, wherein the at least one compound is administered in a composition further comprising at least one excipient.
 11. The method of claim 9, wherein the disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity comprises: inflammatory bowel disease, circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral, vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulation disorder, learning disorder, memory disorder, hippocampal signaling disorder, sleep disorder, attention deficit/hyperactivity disorder, anxiety, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, or bipolar disorder.
 12. The method of claim 10, wherein the disease associated with dysregulation of 5-hydroxytryptamine receptor 7 activity comprises: inflammatory bowel disease, circadian rhythm disorder, depression, schizophrenia, neurogenic inflammation, hypertension, peripheral, vascular diseases, migraine, neuropathic pain, peripheral pain, allodynia, thermoregulation disorder, learning disorder, memory disorder, hippocampal signaling disorder, sleep disorder, attention deficit/hyperactivity disorder, anxiety, avoidant personality disorder, premature ejaculation, eating disorder, premenstrual syndrome, premenstrual dysphonic disorder, seasonal affective disorder, or bipolar disorder. 